CN1330311C - Use of 3,4,5-trihydroxy stilbene-3-beta-D-gluooside in preparation of antimyocardial ischemia medicine - Google Patents
Use of 3,4,5-trihydroxy stilbene-3-beta-D-gluooside in preparation of antimyocardial ischemia medicine Download PDFInfo
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- CN1330311C CN1330311C CNB2004100524709A CN200410052470A CN1330311C CN 1330311 C CN1330311 C CN 1330311C CN B2004100524709 A CNB2004100524709 A CN B2004100524709A CN 200410052470 A CN200410052470 A CN 200410052470A CN 1330311 C CN1330311 C CN 1330311C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The present invention relates to a new function of 3, 4', 5-trihydroxy stilbene-3-beta-D-glucoside as a compound in the preparation of medicines, particularly a function of the compound as an active component in a medicinal composition for treating and/or preventing ischemic heart disease. The medicinal composition has obvious functions of treating or preventing ischemic myocardium and heart function injuries through intravenous injection or oral administration.
Description
Technical field
The present invention relates to 3,4 ', the purposes of 5-trihydroxy stilbene-3-β-D-glycoside relates in particular to the purposes of this chemical compound in treating and/or preventing the ischemic heart desease medication preparation.
Background technology
Chemical compound 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside (3,4 ', 5-trihydroxy-stilbene-3-β-D-glucoside TSG), claims polygonin (polydatin) or picein (peicin) again, and its structure is suc as formula shown in (I):
The sixties in 20th century, 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside at first is found in medicinal plants Rhizoma Polygoni Cuspidati (Polygonumcuspidatum Sieb.et Zucc.), also is found in plants such as storehouse leaf PiceameyeriRehd. Et Wils., Fructus Vitis viniferae, Semen arachidis hypogaeae thereafter.
After the seventies in 20th century, the pharmacological activity of relevant formula (I) chemical compound discovers that it has:
(1) effect for reducing blood fat: for example, hyperlipemia sublingual administration 2.2mg/kg/d can hypercholesterolemia reducing, low-density and high density lipoprotein ratio (.3 such as Zhang Peiwen, 4 ', 5-resveratrol-3-β-D-glycoside is to the influence of human blood rheology and cholesterol, No.1 Military Medical Univ.'s newspaper, 1995; 15 (1): 47～48);
(2) anticoagulant and thrombosis effect: for example, TSG 6-100 μ mol/L can suppress inductive platelet aggregation of arachidonic acid, adenosine diphosphate (ADP) and epinephrine and thromboxance B
2Produce (.3 such as Dan Chunwen, 4,5-resveratrol-3-β-D-glucoside is in the external influence that thromboxance B is assembled and produced to rabbit platelet, Acta Pharmacologica Sinica, 1990,11 (6): 527～530);
(3) positive inotropic action: the shrinkage amplitude of enhancing cultivation myocardial cell and frequency (Jin Chunhua etc. polygonin is to the influence of contractility of cardiac muscle cells, and Chinese Pharmacological is circulated a notice of, and 2000; 16 (4): 400～402);
(4) antioxidation: TSG is to PMNs respiratory burst, xanthine system and VitC-Cu
2+The free radical that system produces have suppress or scavenging action (Tian Jingwei etc. the antioxidation activity in vitro of polydatin, Chinese herbal medicine .2001,32 (10): 918～920);
(5) microcirculation improvement and to the therapeutical effect of shock (Zhao Kesen, Jin Lijuan chief editor. " shock and molecular basis ", Science Press, Beijing, 1989; 319～323).
Ischemic heart desease (ischemic heart disease) is that coronary atherosclerosis makes angiostenosis or obstruction, or/and the functional change of coronary artery (spasm) causes true anoxemia or the downright bad heart disease that causes, general designation coronary atherosclerotic heart disease (coronary atherosclerotic heart disease, CHD), be called for short coronary heart disease.Coronary heart disease is the commonly encountered diseases of serious harm health.Coronary heart disease can be divided into silent myocardial ischemia, angina pectoris, myocardial infarction, ischemic cardiomyopathy, heart failure, the overworked type of waiting indefinitely.
The Therapeutic Method of coronary heart disease comprises Drug therapy, interventional therapy and surgical intervention.At present, clinical the most frequently used medicaments for resisting myocardial ischemia has nitrate esters, beta-blocker and calcium antagonist.Other myocardial ischemic antagonists also have angiotensin-convertion enzyme inhibitor, specificity decreased heart rate medicine etc.The common feature of these medicines is by blood vessel dilating and/or reduces cardiac load, minimizing cardiac work, reduction myocardial oxygen consumption, and then plays the effect of alleviating coronary heart disease symptom.
Nitro vasodilator (nitrovasodilators), or claim nitrate esters medicine, can discharge NO, by the lax vascular smooth muscle of rising cGMP.The nitrate esters medicine of clinical use such as nitroglycerin, sorbide nitrate etc. can be alleviated all kinds of angina pectoriss rapidly usually, and are most widely used in anginal prevention and treatment.Yet, " nitrate esters medicine is a kind of medicine of relief of symptoms; there do not have evidence to show lapsing to be useful; theoretically; such medicine can reflexive be accelerated heart rate, may lapse to negative effect to the long term of myocardial ischemia " (big recklessly first-class chief editor, " following the card angiocardiology ", Tianjin science tech publishing house, 2001).In addition, nitrate esters medicine has increases intracranial pressure, bring out side effect such as glaucoma, and drug resistance can take place rapidly.
Being applied in of calcium antagonist and beta-blocker once had milestone formula meaning in the cardiovascular drugs research field.So far, these medicines remain one of medicine the most frequently used in the coronary heart disease treatment.Calcium antagonist such as nifedipine etc. have the myocardial contraction of inhibition, reduce myocardial oxygen consumption; Remove coronary spasm, improve blood supply of cardiac muscle; The expansion peripheral vessels reduces pharmacotoxicological effects such as cardiac load.Yet a year back finds that this type of medicine can increase myocardial infarction danger surplus the first generation calcium antagonist clinical practice 20.Clinical trial shows " calcium antagonist does not all have the improvement effect to the prognosis of lopsided myocardial infarction, variant angina pectoris and cardiac insufficiency " (Su Dingfeng chief editor, " cardiovascular pharmacology ", Science Press, 2001).
Generally, " conventional anti-cardiac muscle lacks medicine (nitrate, beta-blocker, calcium antagonist) though the energy allevating angina pectoris is not clear to the influence of exertional angina pectoris prognosis "; " also there is not myocardial ischemic antagonist unstable angina pectoris to be lapsed to the data of influence at present "; " fugitive nifedipine increases the mortality rate of acute coronary syndrome, and angiotensin and his class D lipid-lowering medicine have indirect function of resisting myocardial ischemia " (big recklessly first-class chief editor, " following the card angiocardiology ", 2001).
Obviously, although the clinical medicine that is used for coronary heart disease treatment is quite abundant,, still press for clinically safety, effectively, the new coronary heart disease treatment medicine that can effectively improve the prognosis of myocardial ischemia heart disease and lapse to.
As previously mentioned, previously bibliographical information 3,4 ', the cardiac vascular activity of 5-trihydroxy stilbene-3-β-D-glycoside, still, the using value of its embodiment mainly shows Antishock function and hypolipidemic activity.Do not have documents and materials to relate to or point out this chemical compound have function of resisting myocardial ischemia and coronary heart disease treatment and/or the prevention in potential using value.Trace it to its cause and should be:
The cause of disease of coronary heart disease is that coronary stenosis causes blood supply of cardiac muscle to reduce, and produces the imbalance between supply and demand of myocardial blood thus and causes a series of disease symptomses such as pain.Usually, medicaments for resisting myocardial ischemia is conceived to improve patient's hemodynamics feature mostly, particularly reduces cardiac load and the final myocardial oxygen consumption that reduces.Above-mentioned clinical the most frequently used coronary heart disease treatment medicine nitrate esters medicine, calcium antagonist and beta-receptor all have this type of function Characteristics.
And according to existing document, 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside can strengthen the shrinkage amplitude and the contraction frequency of In vitro culture cardiac muscle and isolated heart, increase calcium concentration (Jin Chunhua etc. in the myocardial cell, polygonin is to the influence of contractility of cardiac muscle cells, and Chinese Pharmacological is circulated a notice of, and 2000; 16 (4): 400-402; The gold row is medium, No. 4 influences to rat working heart function of Rhizoma Polygoni Cuspidati crystallization, No.1 Military Medical Univ.'s journal, 1992; 12 (1): 31-33); Obviously, the positive inotropic of this chemical compound and positivity frequency effect mean that the rhythm of the heart that may cause medication person is accelerated, myocardial contraction is strengthened, and its result increases myocardial oxygen consumption, increases the weight of the cardiac muscle burden, the imbalance between supply and demand of aggravation myocardial blood flow.Therefore, according to existing document, be difficult to judge 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside is to the therapeutic value of coronary heart disease, and on the contrary, outwardly, this chemical compound might increase the weight of the imbalance between supply and demand of coronary heart disease myocardial blood flow.
In the existing document about 3,4 ', in the 5-trihydroxy stilbene-3-β-report of D-glycoside to the influence of blood vessel, on the one hand, it is reported 3 of 5.12mM, 4 ', carotid artery and pulmonary artery but 5-trihydroxy stilbene-3-β-D-glycoside diastole rabbit is exsomatized, and 3.28mM does not have significantly effect down; But 1.71mM the vasoconstriction effect of antagonism norepinephrine under the concentration, and do not have significantly effect (Luo Sufang etc., No. 4 diastole effects of Rhizoma Polygoni Cuspidati crystallization, No.1 Military Medical Univ.'s journal, 1992 under the 1.37mM concentration to the Sanguis Leporis seu oryctolagi pipe; 12 (1): 10-13); On the other hand, this chemical compound calcium concentration in the vascular smooth muscle cell that under 0.02mM-2mM concentration, can significantly raise, therefore, direct effect to vascular smooth muscle is positive inotropic action and improves antiotasis (Jin Chunhua etc., Polydatin is to the influence of free calcium concentration in the normal rat smooth muscle cells, Chinese Journal of Pathophysiology, 1998,14 (2): 195-198; Jin Chunhua etc., polygonin are to the regulatory mechanism pre-test of calcium signal in the VSMC, and Chinese Pharmacological is circulated a notice of, and 2000,16 (2): 151-154).Obviously, 5.12mM blood drug level under conventional administration condition, be difficult for to realize: the dog pharmacokinetic that the present invention carried out shows, under the 30mg/kg dosage, the about 100 μ g/ml of moment maximum plasma concentration after the administration, about 0.25mM, in view of the above, desire to reach the blood drug level of 5.12mM, dosage need reach 600mg/kg, the result of study according to the present invention, and this dosage has reached the median lethal dose(LD 50) (LD of animal
50); Comparatively speaking, the blood drug level of 0.02mM-2mM then is the blood drug level that conventional administration can reach.Therefore, infer according to existing document, under conventional administration administration condition, 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside might be to improve antiotasis to the influence of blood vessel, if so, cardiac load should increase, therefore be unfavorable for the alleviation of coronary heart disease symptom.
According to existing document, from hemodynamic effects, be difficult to judge 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside on the contrary, then may draw opposite judgement according to the routine supposition for the useful therapeutical effect of ischemic heart desease.Therefore do not see so far that the resist myocardial ischemia experimental study of aspect also just has been understood that about this chemical compound.
Other has bibliographical information, 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside has protective effect (Luo Sufang etc., 3,4 ' to In vitro culture myocardial cell due to the factors such as chlorpromazine, endotoxin, 5-resveratrol-3-β-D-glycoside is to cultivating the beat influence of frequency and damage of neonatal rat myocardial cell, Acta Pharmacologica Sinica, 1990,11 (2): 147～150; Zhao Qing etc., Polydatin are to the preventive and therapeutic effect of endotoxin induction myocardial cell injury, No.1 Military Medical Univ.'s journal, 2003,3 (4): 364～365).Because this type of research is the chemical injury of In vitro culture myocardial cell, be different from the pathological process and the treatment mechanism of coronary heart disease, therefore, with of the present invention 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside is irrelevant to the therapeutic value of coronary heart disease.
In addition, application number is that 02134928.2 patent application discloses a kind of Pharmaceutical composition that contains Polydatin or its pharmaceutically acceptable salt with microcirculation improvement effect, and the purposes of these compositionss in the medicine of preparation microcirculation improvement.This patent relates to and is used for the treatment of the microcirculation disturbance cardiovascular and cerebrovascular disease.In view of ischemic heart desease is the coronary occlusion disease, but not the microcirculation disturbance of blood capillary, therefore, the treatment of this patent application and ischemic heart desease is irrelevant.
Application number be 02139335.4 patent application relate to mention when polygonin reduces pulmonary hypertension this chemical compound can coronary artery dilating, coronary blood flow increasing because the cited example of this patent application only illustrates that this chemical compound (influences the blood factor TXA of coagulation process to the influence of hypoxia and hypoxia test animal pattern pulmonary artery pressure and to hematology's active factors
2, PGI
2) influence, do not relate to the influence of arteria coronaria and blood flow thereof, and do not see so far about this chemical compound can coronary artery dilating, increase any research document of coronary flow, therefore, the described coronary artery dilating of this patent, increase coronary flow may only be a kind of conjectures, but not strict scientific research result.
Summary of the invention
One object of the present invention is to provide chemical compound 3, and 4 ', the purposes of 5-trihydroxy stilbene-3-β-D-glycoside in preparation treatment or prevention ischemic heart medicine.
Another object of the present invention is to provide and contains 3, and 4 ', the purposes of the pharmaceutical composition of 5-trihydroxy stilbene-3-β-D-glycoside in preparation treatment or prevention ischemic heart medicine.
According to an aspect of the present invention, ischemic heart desease of the present invention comprises the silent myocardial ischemia, angina pectoris, myocardial infarction, ischemic cardiomyopathy, heart failure and overworked waiting indefinitely, when being used for the treatment of or prevent ischemic heart desease, 3,4 ', the consumption of 5-trihydroxy stilbene-3-β-D-glycoside (TSG) according to the treatment effective dose 2mg-30mg/kg body weight of experiment in animal (rat) body/time, according to body surface area convert the dosage obtain human body be the 20-300mg/60kg body weight/time, preferred human body dosage scope be the 50-200mg/60kg body weight/time, corresponding to the 5-20mg/kg body weight dosage of rat.Can give TSG by the mode of oral or venoclysis during treatment.
According to a further aspect in the invention, with 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside is an active ingredient, add pharmaceutically acceptable pharmaceutic adjuvant and the conventional method by this area and can prepare and be used for pharmaceutical composition of the present invention, so the present invention also comprises the purposes of this pharmaceutical composition.When preparation of pharmaceutical compositions of the present invention was become pharmaceutical preparation, the dosage form of pharmaceutical preparation can be: the dosage form of oral administration such as tablet, capsule (comprising hard capsule, soft capsule, enteric coated capsule and microcapsule), powder, granule and syrup; The dosage form of non-oral administration such as injection, suppository, pill, gel and patch.Except that these regular dosage forms, oral fast release solid formulation (for example tablet, granule etc.) and the slow releasing preparation (tablet, granule, fine granular, pill, capsule, syrup, Emulsion, suspension, solution) that is used for oral or non-oral administration can also be used for the present invention.Preparation among the present invention can be the coating or the form of coating not, depends on the needs.The present invention particularly preferably is the dosage form that TSG is used for oral administration and intravenous administration.
Pharmaceutic adjuvant among the present invention comprises the excipient that is used for solid preparation, lubricant, binding agent, disintegrating agent, stabilizing agent, foaming agent, coating materials etc., or be used for solvent, solubilizing agent, suspending agent, isotonic agent, buffer agent, emollient, emulsifying agent of semi-solid preparation, liquid preparation etc., in addition, also can use other medical additive such as antiseptic, antioxidant, coloring agent, sweeting agent and flavoring agent etc. as required.
When pharmaceutical compositions, the content that combination of Chinese medicine is imitated composition TSG is 20mg-300mg, preferred content is 50mg-200mg, this content refers to contain in the medicine that single uses the total amount of TSG, and those skilled in the art can determine the content of TSG in the unit dosage forms (every tablet preparation or every preparation) according to the needs that this content is looked preparation and use.
The present invention proves by a series of experimentation, and the laboratory animal myocardial ischemia all has significant protective effect due to many kinds of reasons of TSG.
It is oral 3,4 ' that the embodiment of the invention 1 has been observed, the influence of the rat heart muscle ischemia that 5-trihydroxy stilbene-3-β-D-glycoside causes pituitrin.Tongue vein fast injection pituitrin 6U/kg can cause rat visceral pericardium and endocardium myocardial ischemia, it mainly shows is that the rat ECG ST section is raised rapidly, after reaching the peak second, about 15-30 descends gradually, the T ripple is low to be put down or is inverted or shows as the ST section and significantly force down, take place frequently the chamber early, and also visible height is to atrioventricular block fully.Test employing 5,10, the administration for three days on end of 20mg/kg dosage, find 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside 10mg/kg and 20mg/kg can significantly reduce anesthesia SD rat intravenous injection pituitrin cause the ECG ST section that myocardial damage causes raise (with matched group relatively, Δ ST has significantly or utmost point significant difference).Show that this chemical compound 10mg/kg and 20mg/kgpo can effectively prevent the rat heart muscle ischemia injury that pituitrin causes.
The embodiment of the invention 2 has observed 3, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside intravenous administration is to the influence of SD rat myocardial ischemia and reperfusion damage.This test is equipped with the myocardial ischemia-reperfusion model with the coronary ligation legal system.Experiment adopt 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside intravenous administration dosage is 7.5,15,30mg/kg (wherein, calculate according to the body surface area method, it is 100mg/ people that dog 7.5mg/kg is equivalent to body weight 70kg human dosage).Result of the test shows that behind the myocardial ischemia-reperfusion, Serum LDH, CK activity obviously increase, and myocardial infarction area weight obviously increases, and with Sham-operated control group significant differences (P＜0.01) is arranged relatively; 3,4 ', the 5-trihydroxy stilbene-3-β-basic, normal, high dosage of D-glycoside (7.5,15,30mg/kg) administration can significantly reduce activity of serum CK, reduce myocardial infarction area weight (with model group relatively, P＜0.05); 3,4 ', the 5-trihydroxy stilbene-3-β-middle and high dosage of D-glycoside (15,30mg/kg) administration can significantly reduce Serum LDH significantly be lower than model group (with model group relatively, P＜0.05); This presentation of results 3; 4 '; 5-trihydroxy stilbene-3-β-D-glycoside intravenous injection has protective effect to rat myocardium from injury due to the ischemia-reperfusion; LDH, CK overflow in the time of can obviously suppressing due to the ischemia-reperfusion rat myocardium from injury; reduce Serum LDH, CK activity; dwindle myocardial infarction area weight, and its drug effect tool dose-dependence.
The embodiment of the invention 3 has observed 3, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside is to the therapeutical effect of myocardial infarction model due to the dog coronary artery ligation.This test also is equipped with the myocardial ischemia-reperfusion model with the coronary ligation legal system.Experiment adopt 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside intravenous administration dosage is 2.5,5,10mg/kg.Result of the test shows, 5min behind the coronary ligation, and solvent control group epicardial electrogram ST section summation (∑ ST) obviously raises, and reaches slowly falling behind the peak (∑ ST raises and reaches 18.2%) during 30min; TSG 2.5～10mg/kg iv can suppress ∑ ST rising in dose dependent ground: 2.5mg/kg dosage group 30～90min and solvent control group significant difference; 5mg/kg organizes each time point and solvent control group, and more all there were significant differences; Remarkable effect is promptly arranged after the administration of 10mg/kg high dose group and continue to 120min.The result shows that TSG 2.5,5, the quiet notes of 10mg/kg have significant therapeutic effect to the acute myocardial ischemia degree that the Canis familiaris L. coronary ligation causes.
Similarly, TSG can dwindle the myocardial ischemia scope in dose dependent ground, reduces epicardial electrogram N-ST value, acts on sustainable 120min.2.5mg/kg each time point N-ST value reduction rate of dosage group and matched group are with time point relatively, 30～90min significant difference (P＜0.05); 5mg/kg dosage group when 15min～120min N-ST value reduction rate and solvent control group relatively there were significant differences with time point; Then it reduces the difference that myocardial ischemia scope and solvent control group relatively have highly significant to 10mg/kg dosage group in the time at 5～120min.
Learn the detection myocardial infarct size with quantitative tissue and promptly show that with N-BT dyeing the quiet notes of TSG 2.5～10mg/kg can reduce myocardial infarct size in dose dependent ground, its result is consistent with the epicardial electrogram measurement result.After TSG 2.5,5, the 10mg/kg administration, the ratio of its infarct/left ventricle and the matched group highly significant (P＜0.01) that relatively descends; The ratio of infarct/whole-heartedly and solvent control group significantly reduce (P＜0.05～0.01).
The serum lactate dehydrogenase (SLD) of each experimental group animal (LDH), creatine kinase (CK) all raise after the coronary artery ligation.And TSG 2.5,5,10mg/kg administration can reduce the rising degree (P＜0.05～0.01) of Serum LDH and CK significantly, and wherein high dose (10mg/kg) drug effect is the strongest.
These experimental results show, 3,4 ', 5-trihydroxy stilbene-3-β-quiet notes of D-glycoside (TSG) can significantly reduce the degree of the myocardial ischemia of coronary ligation dog, dwindle the myocardial ischemia scope, action intensity is dose dependent, and it is consistent that quantitative tissue is learned the result who detects with epicardial electrogram mensuration, proves that the myocardial infarction that the quiet notes of TSG cause the dog coronary artery ligation has the obvious treatment effect.Experimental result also shows, 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside can significantly reduce the degree that serum lactate dehydrogenase (SLD) behind the dog coronary ligation, creatine kinase raise; Point out it can reduce overflowing of acute ischemia myocardial cell LDH, CK, the primary cellular defect when alleviating myocardial ischemia has protective effect to myocardial cell.
The embodiment of the invention 4 has observed 3, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside gastric infusion is to the protective effect of dog acute myocardial infarction.Experimental model is with embodiment 2.3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside adopts oral administration (filling stomach), and dosage is set to 7.5,15 and 30mg/kg respectively.Result of the test shows that TSG 7.5,15 and 30mg/kg po can reduce the ST section that is caused by myocardial ischemia and raise, and TSG 20mg/kg group effect is remarkable; TSG 7.5,15 and 30mg/kgpo can reduce ∑-ST to some extent, and most of the time section ST section has obvious reduction behind the filling stomach; N-ST all descends gradually after TSG 7.5,15 and the 30mg/kg administration, compares significantly reduction in 90 minutes after administration with the solvent control group with the time period; TSG 10,20mg/kg po can significantly reduce the Serum LDH activity; Quantitative tissue is learned (N-BT staining) inspection and is shown that TSG 10,20mg/kg po can significantly dwindle myocardial infarct size.The result of embodiment 4 shows that oral TSG has the myocardial ischemia of alleviating effect; The myocardial damage that the anesthetized dog acute myocardial infarction is caused has protective effect.
The embodiment of the invention 5 has observed 3, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside intravenous administration is to the influence of normal anesthetized dog myocardial oxygen consumption.Result of the test shows: 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside (TSG) 2.5,5, the quiet notes of 10mg/kg back myocardial oxygen consumption are compared there was no significant difference (P＞0.05) with the solvent control group; Can significantly reduce myocardium oxygen uptake rate, reduction rate is compared with time point with the solvent control group, and 2.5mg/kg dosage group is significant difference 15,60, during 90min; 5,10mg/kg dosage group all significantly reduces from 15min to 120min; TSG 2.5,5, the quiet notes of 10mg/kg can increase coronary flow, and increment rate is compared with time point with the solvent control group, and each dosage group is the equal highly significant of difference in 15～120min then.When TSG 5,10mg/kg administration 120min, the coronary resistance reduction rate is compared the difference highly significant with the solvent control group with time point.TSG can increase the dog cardiac output, the cardiac output rate of change is compared with time point with the solvent control group, when 5mg/kg dosage group 60,90min, significant difference when 10mg/kg dosage group 15,30min (P＜0.05), 60, difference highly significant (P＜0.01) during 90min.The above results shows, 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside can obviously increase the anesthetized dog coronary flow, increases cardiac output, can obviously reduce myocardium oxygen uptake rate, reduces coronary resistance.
The embodiment of the invention 6 has observed 3, and 4 ', 5-trihydroxy stilbene-quiet notes administration of 3-β-D-glycoside is to the influence of hemodynamic indexs such as normal anesthetized dog heart rate, blood pressure, heart contraction diastolic function.Result of the test shows: 3,4 ', behind 5-trihydroxy stilbene-3-β-D-glycoside (TSG) 2.5, the 5mg/kg iv, heart rate, blood pressure, left ventricular pressure, the maximum rate of change of left ventricular systolic pressure all have fluctuation, but with administration before there was no significant difference relatively.TSG 10mg/kg iv rising anaesthetized dog blood pressure, but with administration before than there was no significant difference, all other indexs all do not have obvious variation.
The embodiment of the invention 7 has observed 3, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside (TSG) gastric infusion is to the therapeutical effect of rat chronic myocardial ischemia.Test adopts coronary ligation to cause the chronic myocardial ischemia experimental model, and the modeling time was 6 weeks, and after the modeling, the TSG administration cycle was 6 weeks, and dosage is 20mg/kg.Result of the test shows that the mean arterial pressure of ischemic control animal reduces than sham-operation, and the blood pressure of TSG administration animal returns to the sham operated rats level; Ischemic control animal left ventricular LV DP raises than matched group, LVESP, ± the dp/dtmax reduction; And the corresponding hemodynamic index of TSG administration animal all significantly improves; In addition, the ischemic infarction tissue of TSG administration animal significantly reduces than the ischemic control animal.Result of the test shows, 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside (TSG) gastric infusion has significant therapeutical effect to the rat chronic myocardial ischemia.
Studies show that of the embodiment of the invention 8, mouse tail vein injection 3,4 ', the median lethal dose(LD 50) (LD of 5-trihydroxy stilbene-3-β-D-glycoside (TSG)
50) be 648.94mg/kg, its credible 571.18mg/kg～726.70mg/kg that is limited to of 95%.
The embodiment of the invention 9 has been observed single dose 3, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside (TSG) iv is at the intravital pharmacokinetic parameter of dog.The result shows that after the quiet notes of healthy Beagle dog were given TSG 10mg/Kg, 20mg/Kg, 30mg/Kg, the physiological disposition of TSG met two-compartment model, and the curve end is eliminated the half-life (t mutually during its pharmacokinetic parameter medicine
1/2) be respectively 168,152min, 373min; AUC
0～∞Be respectively 315,745 and 1552 μ gmin/ml, AUC and dosage are proportionate substantially, and correlation coefficient r is 0.985.
Above-mentioned studies show that, TSG has tangible function of resisting myocardial ischemia, and therefore, those skilled in that art can understand, and this chemical compound is that coronary heart disease has excellent application value to treating and/or preventing ischemic heart desease.
The inventor proves by series of experimental research, 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside intravenous injection and/or oral administration to myocardial ischemia cardiac muscle due to pituitrin and/or the coronary ligation and cardiac function damage have significant treatment and/preventive effect.Its effect shows treating myocardial ischemia damage degree and the scope due to the reduction ischemia; The Serum LDH enzyme level raises due to the minimizing acute myocardial ischemia; Recover cardiac function infringement due to the chronic myocardial ischemia and alleviate myocardial damage due to the chronic myocardial ischemia.
With the external pharmacology test result of bibliographical information different be that in embodiment of the invention dosage range, TSG has no significant effect heart rate, the cardiac function of normal anesthetized animal.Therefore for living animal, down, TSG does not exist because of just resistant frequency and positive inotropic action cause that myocardium work done increases, and does not cause the remarkable change of myocardial oxygen consumption in these dosage ranges.The inventor discovers, the TSG under the test dose can increase the coronary artery blood flow of experimental animal, reduces coronary resistance, reduces the coronary blood flow oxygen uptake rate, and obviously, these effects help TSG and bring into play its function of resisting myocardial ischemia.And these effects do not see existing documents and materials, can not directly infer according to existing document to draw.
The inventor finds by the pharmacokinetic test, under the used maximal dose 30mg/kg of the present invention, the highest blood drug level that the TSG intravenous injection is obtained is 100 μ g/ml only, about 0.25mmol/L, the drug level (5.25mM) required with direct vasodilator in the in vitro tests differs the above (Luo Sufang etc. of an order of magnitude, No.1 Military Medical Univ.'s journal, No. 4 diastole effects of Rhizoma Polygoni Cuspidati crystallization, 1992 to the Sanguis Leporis seu oryctolagi pipe; 12 (1): 10～13); And desire to reach about 5mM blood drug level, dosage should need to reach 600mg/kg, in fact near the median lethal dose(LD 50) (640mg/kg) of the embodiment of the invention 9 described mice passages through which vital energy circulates administrations, obviously, this is impossible realize to this dosage in actual applications.On the other hand, according to document, TSG 0.02mM～2mM calcium concentration in the vascular smooth muscle cell that can significantly raise, therefore, to the direct effect of vascular smooth muscle should be positive inotropic action and improve antiotasis (Jin Chunhua etc., Polydatin is to the influence of free calcium concentration in the normal rat smooth muscle cells, Chinese Journal of Pathophysiology, 1998,14 (2): 195～198; Jin Chunhua etc., polygonin are to the regulatory mechanism pre-test of calcium signal in the VSMC, and Chinese Pharmacological is circulated a notice of, and 2000,16 (2): 151～154).But embodiment of the invention whole animal experiment showed, that the TSG under the test dose does not make significant difference to Peripheral resistance, illustrates under the present invention resists myocardial ischemia dosage, and TSG is in the body resistance vessel and do not make significant difference.
The inventor also finds, 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside continuous oral administration and all have function of resisting myocardial ischemia by the intravenous route administration.
Thus, the inventor proposes: 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside has useful using value as anti-scheming ischemia medicine in the preparation of coronary heart disease treatment and/or prophylactic agent.
In view of not seeing the report directly related in the existing documents and materials with content of the present invention; Can not embody TSG in assorted potential value aspect resisting myocardial ischemia according to existing basic research data, on the contrary, according to the myocardial cell of In vitro culture and the experimental study result of vascular smooth muscle cell (Jin Chunhua etc. polygonin is to the influence of contractility of cardiac muscle cells, the Chinese Pharmacological circular, 2000,16 (4): 400～402; Jin Chunhua etc., Polydatin is to the influence of free calcium concentration in the normal rat smooth muscle cells, Chinese Journal of Pathophysiology, 1998,14 (2): 195～198; Jin Chunhua etc., Polydatin is to the regulating action of calcium and transmembrane potential in normal person's vascular smooth muscle cell, Chinese Journal of Pathophysiology, 1999; 5 (3): 233～205; Jin Chunhua etc., polygonin are to the regulatory mechanism pre-test of calcium signal in the VSMC, and Chinese Pharmacological is circulated a notice of, 2000,16 (2): infer that 151～154) then TSG may be unfavorable for the hemodynamics improvement under the myocardial ischemia condition, and may increase the weight of the blood flow imbalance between supply and demand of ischemic myocardium.And the inventor finds, under the effective dose that resists myocardial ischemia, the phenomenon of the positive inotropic action of bibliographical information and increase antiotasis does not take place.Obviously, general professional and technical personnel can understand in this area, and content of the present invention is to have novelty and creationary.
Description of drawings
Fig. 1 illustrates the influence of degree of myocardial ischemia (epicardial electrogram ∑ ST) after TSG is to the dog coronary ligation: its vertical coordinate is represented the rate of change of ∑ ST, and abscissa is represented the time behind the coronary ligation.Obviously, compare with the solvent control group, the degree of myocardial ischemia of each administration group of positive control and TSG all has reduction.[seeing embodiment 2 for details]
Fig. 2 illustrates the influence of myocardial ischemia scope (epicardial electrogram N-ST) after TSG is to the dog coronary ligation: its vertical coordinate is represented the rate of change of N-ST, and abscissa is represented the time behind the coronary ligation.Obviously, compare with the solvent control group, the myocardial ischemia scope of each administration group of positive control and TSG all has dwindles.[seeing embodiment 2 for details]
Fig. 3 represents the influence of TSG to anesthetized dog cardiac muscle oxygen uptake rate: its vertical coordinate is represented myocardium oxygen picked-up rate of change (%), and abscissa is represented the time after the administration.As seen from the figure, after each dosage group administration of TSG, the myocardium oxygen uptake rate of anesthetized dog all has reduction.[seeing embodiment 5 for details]
Fig. 4 represents the influence of TSG to the anesthetized dog coronary flow: its vertical coordinate is represented coronary flow rate of change (%), and abscissa is represented the time after the administration.As seen from the figure, after each dosage group administration of TSG, the coronary flow of anesthetized dog all has increase.[seeing embodiment 5 for details]
Fig. 5 represents that TSG is to the kinemic influence of anesthetized dog: its vertical coordinate is represented cardiac output rate of change (%), and abscissa is the time after the administration.As seen from the figure, after the administration of the middle and high dosage group of TSG administration group, the cardiac output of anesthetized dog significantly increases.[seeing embodiment 5 for details]
Fig. 6 represents the blood drug level-time graph behind the quiet notes administration of healthy Beagle dog single dose TSG 10,20, the 30mg/kg: its vertical coordinate is represented blood drug level (μ g/ml), and abscissa is the time after the administration.[seeing embodiment 9 for details]
Hereinafter further specify content of the present invention by specific embodiment.
The specific embodiment
Embodiment 1 is oral 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside causes the influence of rat heart muscle ischemia to pituitrin
It is oral 3,4 ' that the present embodiment purpose is to confirm, the influence of the rat heart muscle ischemia that 5-trihydroxy stilbene-3-β-D-glycoside causes pituitrin.
Medicine and reagent
Be subjected to reagent: 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside granule (lot number 031011), Shenzhen Haiwang Pharmaceutical Co., Ltd's preparation.Be 1.25,2.5 and the suspension of 5mg/ml with the 0.8%CMC compound concentration during administration.
Contrast medicine: Radix Salviae Miltiorrhizae Tabellae (lot number 030926), 300mg/ sheet.Shanghai Leiyun Pharmaceutical Industry Co., Ltd.'s product.Be the suspension of 20mg/ml with the 0.8%CMC compound concentration during administration.
Experimental animal
50 of male SD rats, body weight are 300-425g, are provided by the The 2nd Army Medical College Experimental Animal Center.
Grouping and administration
Test is established 5 groups, comprises the blank group, Radix Salviae Miltiorrhizae Tabellae group (300mg/kg), 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside low (5mg/kg), in (10mg/kg), high (20mg/kg) dosage group.All adopted by reagent and contrast medicine to wait capacity not the isoconcentration mode irritate stomach, the filling gastric capacity is 3ml/kg.3,4 ', the 5-trihydroxy stilbene-3-β-basic, normal, high dosage group of D-glycoside dosage is 5,10 and 20mg/kg.Radix Salviae Miltiorrhizae Tabellae group dosage is 300mg/kg; The blank group waits capacity 0.8%CMC.
Test method
Healthy 50 of male SD rats are divided into 5 groups at random, irritate stomach respectively in continuous three days to give medicine or control solvent, once a day.After the administration in the 3rd day 1 hour, with 3% pentobarbital sodium 30mg/kg intraperitoneal injection of anesthesia, trace the V3 normal ECG (ECG-6511 type electrocardiograph, Shanghai Photoelectricity Medical electron Instrument Co., Ltd.) that leads, the electroactive marker compression set is 1mV=1cm, then gives it up as basic electrocardiographic abnormality.After stablizing 15min, (Shanghai Hefeng Pharmaceutical Co., Ltd. produces tongue vein fast injection pituitrin, lot number 020601.Face with preceding and be made into 0.6U/ml with normal saline) 6U/kg.The injection of record pituitrin is preceding, injection finishes at once, injects back 0.5,1,2,5,10,15,20,30,40,50 and each time point V3 lead electrocardiogram of 60min.Get each time point ST section height statistical disposition, observe the ST section and raise degree (Δ ST, variation mV) and animal dead situation.
Result of the test
(1) general electrocardiogram changes behind the rat injection of pituitrin electrocardiogram and mainly shows as the ST section and raise rapidly behind the intravenous injection pituitrin, about 15-30 reaches the peak second, descend gradually then, the T ripple is low to be put down or is inverted or shows as the ST section and significantly force down, and prompts for visceral pericardium and endocardium myocardial ischemia.Take place frequently the chamber early, and also visible height is to atrioventricular block fully.
(2) being subjected to influence that the reagent thing raises damaging ST section to bring out ST section that damage causes with injection of pituitrin raises degree and changes that (Δ ST mV) is judge index.The result shows, 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside 10mg/kg and 20mg/kg can significantly reduce anesthesia SD rat intravenous injection pituitrin and cause that the ECG ST section that myocardial damage causes raises (table 1).
Conclusion (of pressure testing)
3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside 10mg/kg and 20mg/kg can significantly reduce anesthesia SD rat intravenous injection pituitrin and cause that the ECG ST section that myocardial damage causes raises.Point out this chemical compound 10mg/kg and 20mg/kgpo can more effectively prevent the rat heart muscle ischemia injury that pituitrin causes.
Table 1 TSG to pituitrin bring out SD rat ST section raise the influence of (Δ ST) (
MV, n=10)
| Solvent control | Radix Salviae Miltiorrhizae Tabellae 80mg/kg | TSG 20mg/kg | TSG 10mg/kg | TSG 5mg/kg | |
| 30s after the administration | 0.096±0.063 | 0.056±0.047 | 0.110±0.055 | 0.066±0.22 | 0.075±0.070 |
| 1min after the administration | 0.103±0.071 | 0.078±0.059 | 0.086±0.062 | 0.081±0.063 | 0.078±0.072 |
| 2min after the administration | 0.093±0.062 | 0.076±0.061 | 0.075±0.051 | 0.070±0.055 | 0.083±0.070 |
| 5min after the administration | 0.121±0.071 | 0.080±0.054 | 0.068±0.060 | 0.069±0.067 | 0.056±0.048 * |
| 10min after the administration | 0.142±0.197 | 0.093±0.061 | 0.073±0.061 | 0.083±0.070 | 0.076±0.066 |
| 15min after the administration | 0.158±0.074 | 0.086±0.060 * | 0.059±0.040 ** | 0.066±0.042 ** | 0.076±0.058 * |
| 20min after the administration | 0.135±0.089 | 0.065±0.032 * | 0.049±0.047 * | 0.055±0.046 * | 0.072±0.054 * |
| 30min after the administration | 0.119±0.068 | 0.079±0.058 | 0.041±0.036 ** | 0.074±0.072 | 0.067±0.079 |
| 40min after the administration | 0.137±0.081 | 0.066±0.057 * | 0.052±0.040 ** | 0.069±0.068 | 0.102±0.093 |
| 50min after the administration | 0.160±0.090 | 0.078±0.070 * | 0.066±0.058 * | 0.079±0.073 * | 0.089±0.081 |
| 60min after the administration | 0.174±0.109 | 0.079±0.092 | 0.054±0.046 ** | 0.064±0.056 ** | 0.088±0.069 * |
P＜0.05;
*P＜0.01vs matched group
Embodiment 23, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside iv is to the protective effect of rat myocardial ischemia and reperfusion damage
The purpose of present embodiment is to observe 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside intravenous administration is to the influence of SD rat myocardial ischemia and reperfusion damage.
Be subjected to the reagent thing
Be subjected to reagent: 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside solution (lot number 03030302), 100mg/10ml; Shenzhen Haiwang Pharmaceutical Co., Ltd.Dilute with normal saline during use.
Positive control drug: isosorbidi dinitras injection (isoket ampoule, lot number 479210), Germany is permitted a watt big now pharmaceutical factory and is produced, and the packing of Wa Zi pharmaceutical Co. Ltd is permitted in Zhuhai.
Experimental animal
SPF level SD rat, male, body weight 250～300 grams.No.1 Military Medical Univ. Animal Experimental Study center provides.
Grouping and administration
Sham operated rats, normal saline matched group, isoket ampoule matched group (0.6mg/kg), 3 are established in test, 4 ', 5-trihydroxy stilbene-3-β-D-glycoside low (7.5mg/kg), in (15mg/kg), high (30mg/kg) dosed administration group (the body surface area method is calculated, and it is 100mg that low dosage 7.5mg/kg is equivalent to body weight 70kg human dosage).The femoral vein administration.
Experimental technique
(1) animal surgery and coronary artery ligation method: male SD rat, pentobarbital sodium (45mg/kg ip) anesthesia is faced upward the position and is fixed.With electrocardiograph (ECG-6851C, Shanghai Photoelectricity Medical electron Instrument Co., Ltd.) record II lead electrocardiogram.Tracheal intubation connects artificial respirator.Cut thoracic wall and cut off the four/five rib at intercostal place, breast left side, and happy peplos exposes heart, wears stitching thread under ramus descendens anterior arteriae coronariae sinistrae No. 0/3, stablizes 10min (stable back electrocardiogram deviant discards).Two the end of a thread are passed a bit of thin silica gel tube, knotting is as ischemia ligation (no ST section and T ripple changer eliminate) on the thin silica gel tube of another segment, from the slow drug administration by injection of femoral vein, cut off ligature behind the 40min behind the ischemia 10min, make anterior descending branch pour into 30min again.
(2) mensuration of lactic acid dehydrogenase (LDH), creatine kinase (CK): after perfusion finishes again, abdominal aortic blood, ultraviolet spectrometry is measured Serum LDH, CK activity.
(3) myocardial infarct size algoscopy: under the coronary ligation line, be parallel to coronary sulcus, wait heavy back to cut 5 of ventricular muscles and place nitro blue tetrazolium (N-BT) dye liquor jolting dyeing 15min.Normal myocardium dyes and is skipper, and the infarct cardiac muscle then is not colored as light yellow.Under anatomical lens, separate infarct, weigh respectively, account for the percentage ratio (%) of myocardium weight as the index of weighing infarction size with infarct cardiac muscle weight.
(4) data and statistical procedures respectively organize data with
Expression is carried out significance test with variance analysis.
Result of the test
Behind the myocardial ischemia-reperfusion, Serum LDH, the active obviously increase of CK, myocardial infarction area weight obviously increases, and with Sham-operated control group significant differences (P＜0.01) is arranged relatively; 3,4 ', the 5-trihydroxy stilbene-basic, normal, high dosage group of 3-β-D-glycoside (7.5,15,30mg/kg) activity of serum CK, myocardial infarction area weight are starkly lower than model group (P＜0.05); 3,4 ', the 5-trihydroxy stilbene-middle and high dosage group of 3-β-D-glycoside (15mg/kg, 30mg/kg) Serum LDH significantly is lower than model group (P＜0.05); Isoket ampoule group and 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside administration group is similar, and Serum LDH, CK activity, myocardial infarction area weight obviously reduce (P＜0.05).(table 2)
Conclusion (of pressure testing)
3; 4 '; 5-trihydroxy stilbene-3-β-D-glycoside intravenous injection has protective effect to rat myocardium from injury due to the ischemia-reperfusion; LDH, CK overflow in the time of can obviously suppressing due to the ischemia-reperfusion rat myocardium from injury; reduce Serum LDH, CK activity; dwindle myocardial infarction area weight, and have certain dose-effect relationship.
Table 2 TSG to the influence of ischemia-reperfusion rat blood serum enzymatic activity and myocardial infarction degree (
N=10)
| Group | Dosage | CK(IU/L) | LDH(IU/L) | Infarct ratio (%) |
| Sham operated rats | 1.0ml/kg | 510.8±80.9 | 655.5±78.3 | -- |
| The normal saline group | 1.0ml/kg | 865.4±189.1 ΔΔΔ | 989.9±184.6 ΔΔΔ | 33.73±3.83 ΔΔΔ |
| Different Shu Ji group | 0.6mg/kg | 637.1±100.4 *** | 806.0±92.0 ** | 23.98±3.16 *** |
| 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside group | ||||
| Low dose group | 7.5mg/kg | 710.7±106.8 ** | 857.7±124.0 | 27.57±5.33 *** |
| Middle dosage group | 15.0mg/kg | 630.6±108.6 *** | 809.4±128.4 ** | 24.80±3.32 *** |
| High dose group | 30.0mg/kg | 559.4±72.9 *** | 744.0±149.2 *** | 23.71±3.66 *** |
*P＜0.05,
* *Compare with the normal saline group P＜0.01;
Δ Δ ΔCompare with sham operated rats P＜0.01
Embodiment 33, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside iv is to the therapeutical effect of dog coronary ligation myocardial infarction model
The purpose of present embodiment is to observe 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside causes the therapeutical effect of myocardial infarction model to the dog coronary artery ligation.
Be subjected to the reagent thing
Be subjected to reagent: 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside solution (lot number 03030302), 100mg/10ml; Shenzhen Haiwang Pharmaceutical Co., Ltd.During use, dilute with normal saline.
Positive control drug: isosorbidi dinitras injection (isoket ampoule, lot number 479210), Germany is permitted a watt big now pharmaceutical factory and is produced, and the packing of Wa Zi pharmaceutical Co. Ltd is permitted in Zhuhai.
Experimental animal
Healthy hybrid dog, body weight 10-15kg, male female dual-purpose, No.1 Military Medical Univ.'s Experimental Animal Center provides.
Grouping and administration
Sham operated rats, normal saline matched group, isoket ampoule matched group (0.4mg/kg), 3,4 ' are established in test, 5-trihydroxy stilbene-3-β-D-glycoside low (2.5mg/kg), in (5mg/kg), high (10mg/kg) dosed administration group.Intravenous administration.The administration volume gives saline volume consistent with the ischemia-reperfusion injury model group, administration capacity 2ml/kg.
Test method
After animal is weighed, pentobarbital sodium 30mg/kg iv anesthesia.The circulation of qi promoting cannula connects SC-M5 type anesthesia respirator (Shanghai Medical Instruments factory), waits out row mechanical ventilation (16-18 time/minute, tidal volume 350-550ml) behind the breast.Left border of sternum the 4th intercostal is opened breast, exposes heart, cuts off pericardium and makes the pericardium hammock.Free coronary artery is worn silk thread under it between ramus descendens anterior arteriae coronariae sinistrae second to the 3rd branch, is used for two step ligation.Heart surface is placed 30 visceral pericardium electrodes.Extremity connect 30 visceral pericardium electrodes through needle electrode, are connected to Powerlab system 8s physiograph (ADInstruments) through leading permutator more, write down 30 visceral pericardium electrographs.Adopt Harris two steps ligation method: preceding 2 minutes of ligation first, from the quiet notes lignocaine of femoral artery 5mg/kg prevention arrhythmia.Steel wire with one section diameter 1mm when ligation inserts in first untwisting, with the coronary artery ligation, then extracts steel wire out steel wire.Complete ligation second knot after 30 minutes.
The epicardial electrogram that writes down 10min after the complete ligation as medication before control value, then from the femoral vein administration, negative control group is given with the volume solvent control.Each group all finishes with electronics constant flow pump (the controlled intravenous injection propeller of SH-88AB, medical Electronic Instruments Plant in the Quanzhou City Cyprinus carpio) constant infusion in 30min.Write down after the administration 5,15,30,60,90 and the variation of 120min epicardial electrogram respectively.With the summation (∑ ST) that the ST section raises or leading more than the reduction 2mV counted (NST) and ST section lift-off value is that index observing administration front and back epicardial electrogram changes, and calculating myocardium degree of ischemia (∑ ST) and scope (NST).To compare before different time measured value and the medication after the medication, compare between different time variation percentage rate (being 100% before the medication) is organized after the medication.Ligation is cored dirty after 2 hours, take by weighing weight whole-heartedly; Cut atrium and right ventricle, weigh up left ventricular mass, and under the coronary ligation line, left ventricle is cut into 5 of uniform thickness, clean, put 37 ℃ of dyeing of 0.05% chlorination nitro blue tetrazolium (N-BT) liquid 30 minutes with normal saline.Infarcted region is not painted, and non-infarcted region skipper.The not painted infarcted region of clip is weighed, and calculates infarct weight and accounts for the percentage ratio that reaches left ventricular mass whole-heartedly.Respectively got right ventricle blood 3ml in 2 hours before the coronary ligation and after the administration, centrifugal 15 minutes of 3000rpm gets serum and surveys lactic acid dehydrogenase (LDH), serum creatine kinase (CK).The mensuration employing LDH testing cassete method of LDH (lot number: 20020523, bio-engineering research institute is built up in Nanjing), CK (ENR:U90625, Randox company, UK).On UV751GD type ultraviolet spectrophotometer, carry out (Shanghai analytical tool factory).
Result of the test
(1) 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside (TSG) is to the influence of degree of myocardial ischemia (epicardial electrogram ∑ ST): 5min behind the coronary ligation, the outer electrograph ST section summation (∑ ST) of the solvent control group heart obviously raises.∑ ST raises and reaches 18.2% during solvent control group 30min, after this slowly falls after rise; Can alleviate degree of myocardial ischemia in dose dependent ground behind the TSG 2.5-10mg/kg intravenously administrable, ∑ ST significantly descends: low dose group 30-90min and solvent control group significant difference; More all there were significant differences for middle each time point of dosage group and solvent control group; Remarkable effect is promptly arranged after the high dose group administration and continue to 120min.5 to 90min, ∑ ST's isoket ampoule group descends, but after 90s to 120min and solvent control group there was no significant difference after administration.Experimental result shows that TSG 2.5,5, the quiet notes of 10mg/kg have significant therapeutic effect to the acute myocardial ischemia degree that the Canis familiaris L. coronary ligation causes.Experimental result sees Table 3, Fig. 1.
(2) 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside (TSG) can dwindle the myocardial ischemia scope in dose dependent ground to the influence of myocardial ischemia scope (epicardial electrogram N-ST): TSG, reduces the N-ST value, acts on sustainable 120min.Each time point N-ST value reduction rate of low dose group 2.5mg/kg and solvent control group compare with time point, 30-90min significant difference (P＜0.05); In dosage group 5mg/kg when 15min-120min N-ST value reduction rate and solvent control group there were significant differences with the time point comparison; It reduces the difference that myocardial ischemia scope and solvent control group relatively have highly significant to high dose group (10mg/kg) in time at 5-120min.Isoket ampoule group 5min myocardial ischemia scope and solvent control group after administration more also have remarkable decline with time point.Experimental result sees Table 4, Fig. 2.
(3) 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside (TSG) is learned the influence that detects to the quantitative tissue of myocardial infarct size: learn the detection myocardial infarct size with quantitative tissue and promptly show 3 with N-BT dyeing, 4 ', 5-trihydroxy stilbene-3-β-D-glycoside is consistent with the result of epicardial electrogram mensuration to the influence of myocardial infarct size.The quiet notes of TSG 2.5～10mg/kg can reduce myocardial infarct size in dose dependent ground.The ratio of the basic, normal, high dosage group of TSG (2.5,5,10mg/kg) stalk infarct/left ventricle and the solvent control group highly significant (P＜0.01) that relatively descends; The ratio of infarct/whole-heartedly and solvent control group relatively, low dose group descends significantly (P＜0.05), middle and high dosage group decline highly significant (P＜0.01).Wherein the high dose group effect is the strongest.The isoket ampoule group is also significantly dwindled myocardial infarct size (P＜0.01).Experimental result sees Table 5.
(4) 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside (TSG) is to the influence of serum biochemical indicator behind the coronary ligation: respectively organize serum lactate dehydrogenase (SLD) (LDH) after the coronary artery ligation, creatine kinase (CK) all raises.Basic, normal, high dosage group of TSG and positive control drug group be the rising degree (P＜0.01) of the reduction Serum LDH of energy highly significant all; Middle and high dosage group and positive control drug group be the rising degree (P＜0.01) of the reduction serum CK of energy highly significant all, and low dose group can reduce the rising degree (P＜0.05) of serum CK significantly.Wherein high dose group (10mg/kg) drug effect is the strongest.Experimental result sees Table 6.
Conclusion (of pressure testing)
Experimental result proves, 3,4 ', 5-trihydroxy stilbene-3-β-quiet notes of D-glycoside (TSG) can significantly reduce the degree of the myocardial ischemia of coronary ligation dog, dwindle the myocardial ischemia scope, and action intensity is dose dependent, it is consistent that quantitative tissue is learned the result who detects with epicardial electrogram mensuration, compare with the solvent control matched group, infarct significantly dwindles, and proves that the myocardial infarction that the quiet notes of TSG cause the dog coronary artery ligation has the obvious treatment effect.Experimental result also shows, 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside can significantly reduce the degree that serum lactate dehydrogenase (SLD) behind the dog coronary ligation, creatine kinase raise; Point out it can reduce overflowing of acute ischemia myocardial cell LDH, CK, the primary cellular defect when alleviating myocardial ischemia has protective effect to myocardial cell.
Table 3 TSG to the influence of dog coronary ligation epicardial electrogram ST section summation (∑ ST) (mV,
N=6)
*P＜0.05,
*＜0.01 with the solvent control group relatively
Table 4 TSG to the influence of dog coronary ligation myocardial infarct size (N-ST) (
N=6)
*P＜0.05,
*Compare with the solvent control group P＜0.01
Table 5 TSG to N-BT dyeing measure myocardial infarct size influence (
N=6)
| Group | Infarct/(%) whole-heartedly | Infarct/left ventricle (%) |
| Solvent control 2ml/kg | 14.84±2.18 | 26.15±1.55 |
| Different Shu Ji 0.4mg/kg/h | 9.57±2.48 * | 15.47±3.80 ** |
| TSG 2.5mg/kg | 11.70±0.93 * | 21.68±1.88 ** |
| TSG 5.0mg/kg | 9.03±1.16 ** | 15.25±1.41 ** |
| TSG 10mg/kg | 8.65±1.11 ** | 13.92±1.32 ** |
*P＜0.05,
*Compare with the solvent control group P＜0.01
Table 6 TSG to the influence of coronary ligation tremulous pulse serum biochemical indicator (
N=6)
| Group | LDH(IU/L) | CK(IU/L) | ||||
| Before the administration | After the administration | Back/preceding | Before the administration | After the administration | Back/preceding | |
| Solvent control 2ml/kg | 326.8±55.1 | 919.6±211.2 | 2.81±0.35 | 171.3±25.8 | 526.2±102.9 | 3.07±0.37 |
| Different Shu Ji 0.4mg/kg/h | 330.0±78.4 | 563.1±133.3 | 2.03±0.22 ** | 172.7±13.2 | 360.2±51.9 | 2.09±0.25 ** |
| TSG 2.5mg/kg | 359.7±70.5 | 823.3±186.3 | 2.28±0.21 ** | 176.7±18.8 | 446.6±39.4 | 2.54±0.27 * |
| TSG 5.0mg/kg | 281.2±80.9 | 587.1±170.6 | 2.09±0.16 ** | 180.8±13.2 | 356.2±64.8 | 1.98±0.38 ** |
| TSG 10mg/kg | 279.3±70.8 | 551.6±131.3 | 1.99±0.14 ** | 172.7±11.1 | 299.5±63.9 | 1.74±0.37 ** |
*P＜0.05,
*Compare with the solvent control group P＜0.01
The purpose of present embodiment is to observe 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside is irritated the protective effect of stomach to the dog acute myocardial infarction.
Trial drug
Be subjected to reagent: 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside granule (lot number 031019), Shenzhen Haiwang Pharmaceutical Co., Ltd's preparation.During administration with the 0.8%CMC compound concentration be 1,2, the suspension of 4mg/ml.
Contrast medicine: Radix Salviae Miltiorrhizae Tabellae (lot number 030926), 300mg/ sheet.Shanghai Leiyun Pharmaceutical Industry Co., Ltd.'s product.Be the suspension of 9mg/ml with the 0.8%CMC compound concentration during administration.
Experimental animal
30 of healthy hybrid dogs, male female dual-purpose, body weight 12～14kg, No.1 Military Medical Univ.'s Experimental Animal Center provides.
Grouping and administration
Solvent control group, positive controls (Radix Salviae Miltiorrhizae Tabellae 45mg/kg), 3,4 ', 5-trihydroxy stilbene-3-β-D- glycoside 5,10 and 20mg/kg dosage group are established in test.Capacity such as administering mode employing are the isoconcentration gastric infusion not, irritates the stomach volume to be: 5ml/kg.Below respectively organize all gastric infusions after the every index that is write down is stablized 30 minutes of medicine.
Experimental technique
After weighing, animal anaesthetizes with 3% pentobarbital sodium 30mg/kg intravenous injection.Tracheal intubation connects anesthesia respirator (SC-M5 type, Shanghai Medical Instruments factory), and (18～20 times/minute, air-breathing ratio with expiration is 1: 2, tidal volume 350～550ml) to open behind the breast row mechanical ventilation.With needle electrode insert extremity and the front subcutaneous, the monitoring standard limb is led and V3, electrocardiogram.Open breast along left border of sternum the 3rd intercostal, and cut off the 4th rib and fully expose heart.Cut off pericardium and make the pericardium hammock.Free coronary artery is worn silk thread under it between ramus descendens anterior arteriae coronariae sinistrae second to the 3rd branch, is used for two step ligation.Heart surface is placed 30 visceral pericardium electrodes.Extremity connect 30 visceral pericardium electrodes through needle electrode, are connected to Powerlab system 8s physiograph (AD Instruments) through leading permutator more, the record epicardial electrogram.
Cause the acute myocardial ischemia model with two step ligation methods, preceding 2 minutes of ligation first is from the quiet notes lignocaine of femoral artery 5mg/kg prevention arrhythmia.After giving normal saline or being subjected to the reagent thing 5,15,30,60,90,120, the epicardial electrogram of 30 mapping points of 180min record, raising greater than 2mV with the ST section is criterion, and (the ST section raises, and (the ST section raises and surpasses the total points N of 2mV-ST) for total millivolt number ∑-ST) and myocardial ischemia scope with this calculating myocardium degree of ischemia.From femoral vein blood drawing 4ml, put centrifuge behind the 180min, 10000 rev/mins centrifugal 5 minutes, leave and take serum-18 and ℃ preserve LDH to be measured (LDH test kit, lot number: 20020523, bio-engineering research institute is built up in Nanjing).It is dirty to core, and claims weight whole-heartedly, cuts off weigh behind auricle and the right ventricle (Zuo Xinchong).With the thick myocardium sheet of the anxious one-tenth 0.5～1cm in a left side, clean then, put 37 ℃ of 0.025% chlorination nitro blue tetrazolium (Switzerland Fluka chemical reagents corporation produces NBT for Nitro-tetrazoliumBlue chloride, N-BT) liquid dyeing with normal saline.Infarcted myocardium is not painted, and non-infarcted myocardium is being dyed black-and-blue, and the uncoloured infarcted region of clip is weighed.
Experimental result with
Non-paired t test method statistics is adopted in expression, and P＜0.05 o'clock thinks to have notable statistics difference.
Result of the test
(1) TSG influences anesthetized dog heart rate (surface electrocardiogram): relatively do not have significant change (table 6) before and after solvent control group, positive controls and the medication of 3 dosage groups of TSG;
The oral TSG of table 6 to the influence of anesthetized dog heart rate (
Inferior/minute, n=6)
| The solvent control group | Radix Salviae Miltiorrhizae Tabellae group 45mg/kg | TSG 5mg/kg | TSG 10mg/kg | TSG 20mg/kg | |
| Before the administration | 164±15 | 170±12 | 173±16 | 169±12 | 185±10 |
| 5min after the administration | 161±12 | 176±13 | 174±18 | 169±11 | 186±13 |
| 15min after the administration | 167±17 | 175±11 | 168±17 | 167±10 | 182±11 |
| 30min after the administration | 164±18 | 173±14 | 170±16 | 165±12 | 184±12 |
| 60min after the administration | 168±16 | 167±13 | 167±12 | 163±16 | 178±16 |
| 90min after the administration | 165±11 | 168±16 | 165±12 | 165±12 | 177±15 |
| 120min after the administration | 166±18 | 172±13 | 167±13 | 162±11 | 180±21 |
| 180min after the administration | 169±18 | 164±16 | 163±12 | 159±14 | 168±19 |
(2) TSG influence that myocardial ischemia dog surface electrocardiogram ST section is raised degree (Δ ST): each dosage of Radix Salviae Miltiorrhizae Tabellae and TSG is irritated and can be reduced the ST section that is caused by myocardial ischemia behind stomach and raise TSG 20mg/kg group effect significantly (table 7).
The oral TSG of table 7 to the influence of dog Δ ST (
MV, n=6)
| The solvent control group | Radix Salviae Miltiorrhizae Tabellae group 45mg/kg | TSG 5mg/kg | TSG 10mg/kg | TSG 20mg/kg | |
| 5min after the administration | 1.10±0.60 | 0.41±0.34 * | 0.66±0.45 | 0.55±0.40 | 0.58±0.30 |
| 15min after the administration | 1.04±0.63 | 0.77±0.42 | 0.170±0.50 | 0.68±0.51 | 0.45±0.17 * |
| 30min after the administration | 1.21±0.80 | 0.60±0.30 | 0.71±0.48 | 0.69±0.52 | 0.39±0.16 * |
| 60min after the administration | 1.09±0.48 | 0.71±0.43 | 0.73±0.51 | 0.69±0.45 | 0.35±0.19 * |
| 90min after the administration | 1.30±0.75 | 0.69±0.44 | 0.88±0.54 | 0.70±0.44 | 0.26±0.15 ** |
| 120min after the administration | 1.32±0.68 | 0.64±0.38 | 0.82±0.49 | 0.75±0.46 | 0.28±0.13 ** |
| 180min after the administration | 1.40±0.71 | 0.55±0.33 * | 0.86±0.52 | 0.81±0.52 | 0.23±0.16 ** |
*P＜0.05,
*P＜0.01 vs solvent control group
(3) TSG to the anesthetized dog acute myocardial ischemia (influence of epicardial electrogram ∑-ST): with the solvent control group relatively, each administration group ∑-ST all has in various degree and reduces, irritate stomach after most of the time section ST section obvious reduction (table 8) is arranged.
The oral TSG of table 8 to the dog degree of myocardial ischemia (influence of ∑-ST) (
MV, n=6)
| The solvent control group | Radix Salviae Miltiorrhizae Tabellae group 45mg/kg | TSG 5mg/kg | TSG 10mg/kg | TSG 20mg/kg | |
| Before the administration | 55.6±9.11 | 59.2±7.03 | 55.7±6.14 | 54.3±1.89 | 62.1±6.34 |
| 5min after the administration | 92.1±12.8 | 82.0±13.7 | 77.3±15.0 | 77.9±10.6 | 78.7±5.68 * |
| 15min after the administration | 95.0±8.23 | 77.9±14.7 * | 77.9±13.9 * | 69.6±7.90 *** | 77.8±8.49 ** |
| 30min after the administration | 93.0±6.81 | 72.2±12.7 ** | 71.6±8.71 *** | 69.8±7.32 *** | 70.6±4.79 *** |
| 60min after the administration | 87.3±5.59 | 70.9±10.9** | 72.2±8.68** | 75.9±16.3 | 68.7±6.25 *** |
| 90min after the administration | 90.6±11.4 | 69.1±12.4 * | 70.5±8.46 ** | 68.8±7.83 ** | 65.7±7.12 ** |
| 120min after the administration | 89.1±5.58 | 66.0±7.68 *** | 73.6±8.00 ** | 66.3±5.60 *** | 65.0±6.12 *** |
| 180min after the administration | 82.4±8.82 | 61.7±5.17 *** | 67.4±8.19 * | 64.2±5.45 ** | 62.5±3.03 *** |
*P＜0.05,
*P＜0.01,
* *P＜0.001 vs solvent control group
(4) TSG is to the influence of anesthetized dog acute myocardial ischemia scope (epicardial electrogram N-ST): surpass percentage ratio (N-ST) expression of 2mV with ST section in 32 electrodes.N-ST changes not obviously after the administration of solvent control group, and N-ST all descended gradually after Radix Salviae Miltiorrhizae Tabellae group and TSG respectively organized medication, relatively significantly reduces (table 9) with the solvent control group in 90 minutes with the time period after administration.
The oral TSG of table 9 to the influence of dog N-ST (
%, n=6)
| The solvent control group | Radix Salviae Miltiorrhizae Tabellae group 45mg/kg | TSG 5mg/kg | TSG 10mg/kg | TSG 20mg/kg | |
| Before the administration | 34.6±13.7 | 35.2±19.3 | 26.5±17.6 | 22.8±9.44 | 42.3±20.6 |
| 5min after the administration | 85.6±19.3 | 86.4±13.69 | 70.3±21.4 | 79.5±19.5 | 89.2±20.3 |
| 15min after the administration | 79.6±14.3 | 81.1±16.3 | 66.9±19.8 | 72.3±15.9 | 78.9±13.7 |
| 30min after the administration | 81.0±15.5 | 76.1±16.2 | 70.3±16.3 | 69.4±13.2 | 74.9±12.9 |
| 60min after the administration | 85.2±8.03 | 66.3±19.8 | 69.5±15.8 | 68.0±18.8 | 67.2±16.5 |
| 90min after the administration | 86.3±9.89 | 68.9±16.6 * | 63.0±18.7 * | 68.6±15.6 * | 59.2±18.9 * |
| 120min after the administration | 83.4±8.69 | 57.9±16.8 * | 63.2±12.8 * | 61.9±14.9 * | 56.4±13.6 ** |
| 180min after the administration | 80.1±17.2 | 49.6±18.6 ** | 58.3±19.3 | 55.5±16.7 * | 46.8±14.9 ** |
The ST section surpasses the percentage ratio of 2mV in N-ST:32 electrode;
*P＜0.05,
*P＜0.01 vs solvent control group.
(5) TSG to the anesthetized dog acute myocardial infarction after the influence of serum zymetology and solvent control group relatively, behind the gastric infusion, TSG 10,20mg/kg can significantly reduce LDH activity (table 10).
The oral TSG of table 10 to the anesthetized dog acute myocardial infarction after LDH influence (
IU/L, n=6)
| Solvent control | Radix Salviae Miltiorrhizae Tabellae 45mg/kg | TSG 5mg/kg | TSG 10mg/kg | TSG 20mg/kg | |
| LDH | 206±47.3 | 173±81.4 | 159±80.4 | 140±47.6 ** | 120±40.0 ** |
*P＜0.01 vs solvent control group
(6) TSG to the anesthetized dog acute myocardial infarction after the quantitative tissue that influences of myocardial infarct size learn (N-BT staining) and check and show, with the solvent control group relatively, Radix Salviae Miltiorrhizae Tabellae group, TSG respectively organize myocardial infarct size and all significantly dwindle (table 11).
The oral TSG of table 11 to the influence of anesthetized dog acute myocardial infarction scope (
G, n=6)
| The solvent control group | Radix Salviae Miltiorrhizae Tabellae group 45mg/kg | TSG 5mg/kg | TSG 10mg/kg | TSG 20mg/kg | |
| Cardiac weight (g) | 68.3±11.6 | 78.7±15.6 | 79.7±6.68 | 68.8±6.05 | 80.6±13.3 |
| Zuo Xinchong (g) | 46.2±9.26 | 53.8±10.8 | 55.1±4.15 | 48 2±4.84 | 56.2±9.58 |
| Infarcted myocardium heavy (g) | 4.58±0.83 | 3.67±0.98 * | 5.98±1.71 | 3.17±0.66 * | 2.31±0.70 ** |
| Infarcted myocardium weight/Zuo Xinchong | 9.96±1.68 | 6.94±1.67 * | 10.8±2.81 | 6.61±1.31 ** | 4.03±0.61 *** |
*P＜0.05,
*P＜0.01,
* *P＜0.001 vs solvent control group
Conclusion (of pressure testing)
(1) 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside by 5,10 and the 20mg/kg gastric infusion can reduce surface electrocardiogram and the epicardial electrogram ST section that myocardial ischemia causes after the big coronary artery ligation and raise degree, illustrate that oral this chemical compound has the myocardial ischemia of alleviating effect;
(2) the N-BT staining shows, and is oral 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside 10 and 20mg/kg can significantly alleviate anesthetized dog acute myocardial ischemia degree and dwindle myocardial infarct size; The active detection of LDH shows; oral 3; 4 '; but the activity of LDH behind 5-trihydroxy stilbene-3-β-D- glycoside 5,10 and the 20mg/kg dose dependent ground inhibition dog acute myocardial infarction; point out oral 3; 4 ', 5-trihydroxy stilbene-3-β-D-glycoside has protective effect to the myocardial damage that the anesthetized dog acute myocardial infarction causes.
Embodiment 53, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside iv is to the influence of anesthetized dog myocardial oxygen consumption
The purpose of present embodiment is experimental observation 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside intravenous administration is to the influence of anesthetized dog myocardial oxygen consumption.
Be subjected to the reagent thing
Be subjected to reagent: 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside solution (lot number 03030302), 100mg/10ml; Shenzhen Haiwang Pharmaceutical Co., Ltd.During use, dilute with normal saline.
The contrast medicine: isosorbidi dinitras injection (isoket ampoule, lot number 479210), Germany is permitted a watt big now pharmaceutical factory and is produced, and the packing of Wa Zi pharmaceutical Co. Ltd is permitted in Zhuhai.
Experimental animal
Healthy hybrid dog, body weight 10～14kg, male female dual-purpose, No.1 Military Medical Univ.'s Experimental Animal Center provides.
Grouping and administration
Solvent control group, different Shu Ji matched group (0.4mg/kg/h), 3,4 ' are established in test, 5-trihydroxy stilbene-3-β-D-glycoside low (2.5mg/kg), in (5mg/kg), high (10mg/kg) dosed administration group.The administration of different Shu Ji matched group continuous intravenous infusion, other respectively organizes intravenous administration.
Test method
Give the dog intravenous anesthesia with 3% pentobarbital sodium 30mg/kg, tracheal intubation also is connected to SC-M5 type anesthesia respirator (Shanghai Medical Equipment Factory, frequency 16～18 times/minute, tidal volume 350～550ml).Separate the both sides femoral artery, be respectively applied for and get haemanalysis and measure mean blood pressure.Left side the 4th intercostal is opened breast, exposes heart, cuts off pericardium, makes the pericardium bed.Free root of ascending aorta and ramus descendens anterior arteriae coronariae sinistrae top are placed electromagnetic flowmeter probe (MFV-1100/1200 type, Japanese Nihon Kohden company) the thought-read output and the coronary flow of suitable internal diameter respectively.Separate right external jugular vein, insert cardiac catheter and guide cardiac catheterization coronary sinus vein, fixedly cardiac catheter.Get synchronously coronary sinus and femoral artery blood specimen (0.5% anticoagulant heparin), (DH-1830 type vim and vigour acid alkali analyser, Nanjing analytical tool factory) measures pO with blood gas analyzer
2, pH is converted into tremulous pulse and venous oxygen content.Quiet gives solvent control or medicine, and each group all finishes with electronics constant flow pump (the controlled intravenous injection propeller of SH-88AB, medical Electronic Instruments Plant in the Quanzhou City Cyprinus carpio) constant infusion in 30min.Analyze before the administration and tremulous pulse and venous blood gas after the administration 5,15,30,60,90, during 120min, and observe 0,5,15,30,60,90, mean blood pressure and cardiac output during 120min.When experiment finishes heart is weighed, and be poured into the electromagnetic flowmeter survey position with lower area with the senior burnt black ink adverse current in 10-15ml 10% Shanghai, cutting-out is dyed the black area and is weighed, and is used for the calculating myocardium oxygen consumption.Before calculating administration, after the administration 5,15,30,60,90,120min myocardial oxygen consumption figureofmerit.Formula is:
Myocardial oxygen consumption (ml/min/100g)=coronary flow ml/min/100g * (arterial blood oxygen ml%-coronary sinus blood oxygen ml%).
Cardiac muscle oxygen uptake rate (%)=(arterial blood oxygen ml%-coronary sinus blood oxygen ml%)/arterial blood oxygen ml%
Body circulation total peripheral resistance (dynscm
-5)=mean arterial pressure [MAP (KPa)] * 80/ cardiac output [CO (L/min)]
=mean arterial pressure [MAP (mmHg)] * 10.6/ cardiac output [CO (L/min)]
Coronary resistance [Kpa/ml/min]=mean arterial blood pressure [MAP (KPa)]/coronary flow [(mL/min)]
Result of the test
(1) to the influence of anesthetized dog myocardial oxygen consumption: 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside (TSG) 2.5,5, the quiet notes of 10mg/kg back myocardial oxygen consumption are compared there was no significant difference (P＞0.05) with the solvent control group, the results are shown in Table 12.
(2) to the influence of anesthetized dog cardiac muscle oxygen uptake rate: 3,4 ', can significantly reduce myocardium oxygen uptake rate behind 5-trihydroxy stilbene-3-β-quiet notes of D-glycoside (TSG).Reduction rate is compared with time point with the solvent control group, and small dose group is significant difference 15,60, during 90min; Middle and high dosage group reduces than the equal highly significant of myocardium oxygen uptake rate with the solvent control group from 15min to 120min.The results are shown in Table 13, Fig. 3.
(3) to the influence of anesthetized dog coronary flow: 3,4 ', 5-trihydroxy stilbene-3-β-each dosage group of D-glycoside (TSG) can increase coronary flow; Increment rate is compared with time point with the solvent control group, and small dose group is from 15min significant difference (P＜0.05), 30～90min difference highly significant (P＜0.01); Middle and high dosage group is then from the equal highly significant of 15～120min difference.The results are shown in Table 14, Fig. 4.
(4) to the influence of anesthetized dog coronary resistance: coronary resistance does not have significance and changes difference highly significant (P＜0.01) when middle and high dosage group coronary resistance reduction rate is compared 120min with the solvent control group with time point during each dosage group 5～90min of TSG injection.The results are shown in Table 15.
(5) to the influence of anesthetized dog cardiac output, Peripheral resistance: TSG can increase the dog cardiac output, the cardiac output rate of change is compared with time point with the solvent control group, when middle dosage group 60,90min, significant difference when high dose group 15,30min (P＜0.05), 60, difference highly significant (P＜0.01) during 90min.Positive controls does not make significant difference to cardiac output.TSG does not make significant difference to Peripheral resistance.The results are shown in Table 16,17 and Fig. 5.
6 conclusions
3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside can obviously increase the anesthetized dog coronary flow, increases cardiac output, can obviously reduce myocardium oxygen uptake rate, reduces coronary resistance; Myocardial oxygen consumption, Peripheral resistance there is not obvious influence.
Table 12 TSG iv is to the influence (mL/min.100g of dog myocardial oxygen consumption
-1,
N=6)
*P＜0.05,
*Compare with the solvent control group P＜0.01
Table 13 TSG iv to the influence of dog cardiac muscle oxygen uptake rate (%,
N=6)
*P＜0.05,
*Compare with the solvent control group P＜0.01
Table 14 TSG to the influence of dog coronary flow (ml/min,
N=6)
*P＜0.05,
*Compare with the solvent control group P＜0.01
Table 15 TSG to the influence of dog coronary resistance (Kpa/ml/min,
N=6)
*P＜0.05,
*Compare with the solvent control group P＜0.01
Table 16 TSG to the influence of dog cardiac output (CO) (L/min,
N=6)
*P＜0.05,
*Compare with the solvent control group P＜0.01
Table 17 TSG is to influence (TPR, the dynscm of total peripheral resistance
-5,
N=6)
*P＜0.05,
*Compare with the solvent control group P＜0.01
Embodiment 63, and 4 ', 5-resveratrol-3-β-D-glucose iv is to the hemodynamic influence of anesthetized dog
The purpose of present embodiment is experimental observation 3,4 ', and 5-resveratrol-quiet notes administration of 3-β-D-glycoside is to the influence of hemodynamic indexs such as normal anesthetized dog heart rate, blood pressure, heart contraction diastolic function.
Be subjected to the reagent thing
Be subjected to reagent: 3,4 ', 5-resveratrol-3-β-D glycoside solution (lot number 03030302), 100mg/10ml; Shenzhen Haiwang Pharmaceutical Co., Ltd.During use, dilute with normal saline.
The contrast medicine: isosorbidi dinitras injection (isoket ampoule, lot number 479210), Germany is permitted a watt big now pharmaceutical factory and is produced, and the packing of Wa Zi pharmaceutical Co. Ltd is permitted in Zhuhai.
Experimental animal
Healthy hybrid dog, body weight 10-14kg, male female dual-purpose, No.1 Military Medical Univ.'s Experimental Animal Center provides.
Grouping and administration
Solvent control group, different Shu Ji matched group (0.4mg/kg/h), 3,4 ', 5-resveratrol-3-β-D-glycoside low (2.5mg/kg), in (5mg/kg), high (10mg/kg) dosed administration group.The administration of different Shu Ji matched group continuous intravenous infusion, other respectively organizes intravenous administration.
Test method
After dog was anaesthetized with pentobarbital sodium, it was fixing to lie on the back, the circulation of qi promoting cannula; Separate femoral catheter record arteriotony, cardiac catheter is driven in the wrong direction from right carotid and is inserted left ventricle.Two conduits connect pressure transducer, and pressure signal is connected to Powerlab system 8s physiograph (ML785/8S, AD Instruments, Australia) after carrier wave amplifies.The subcutaneous insertion needle electrode of extremity monitoring standard two lead electrocardiogram.Data are monitored and stored to computer (chan4.12 software, ML785/8S, AD Instruments, Australia) in real time.Stablized basic value before the record administration after the operation 30 minutes.Negative control group intravenous injection solvent control 2ml/kg, the quiet instillation 0.4mg/kg/h of positive controls, administration group intravenous injection TSG solution (constant infusion finishes in 30min for the controlled intravenous injection propeller of SH-88AB, medical Electronic Instruments Plant in the Quanzhou City Cyprinus carpio).The record administration after 10,30,60, the every desired value of 120min.
Observation index comprise examine the maximum rate of change of heart rate (HR), systolic pressure (BPs), diastolic pressure (BPd), mean arterial pressure (BPm), left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), left ventricular systolic pressure (± dp/dtmax), ventricular end diastolic pressure (LVEDP), electrocardiogram.
Result of the test with
Expression is carried out variance analysis with SPSS 10.0 softwares, makes significance test of difference.
Result of the test
The result shows: 3,4 ', behind 5-resveratrol-3-β-D glycoside (TSG) 2.5mg/kg, 5mg/kg iv, heart rate, blood pressure, left ventricular pressure, the maximum rate of change of left ventricular systolic pressure all have fluctuation, but with administration before there was no significant difference relatively.TSG10mg/kg iv rising anaesthetized dog blood pressure, but with administration before than there was no significant difference, all other indexs all do not have obvious variation.
The results are shown in Table 18～22.
Table 18 solvent 2ml/kg iv to the hemodynamic effect of anesthetized dog (
N=5)
| |
0 | 10 | 30 | 60 | 120 |
| HR (inferior/minute) | 169.5±29.5 | 171.8±28.4 | 170.6±24.9 | 179.7±42.6 | 168.0±32.4 |
| BPs(KPa) | 23.0±3.9 | 22.6±3.3 | 23.1±3.0 | 24.2±2.8 | 23.3±2.2 |
| BPm(KPa) | 19.0±3.7 | 19.0±2.9 | 19.5±3.0 | 20.5±2.8 | 19.6±2.1 |
| BPd(KPa) | 16.7±3.4 | 16.6±2.6 | 17.2±3.1 | 18.1±3.1 | 17.1±2.3 |
| LVSP(KPa) | 23.5±4.5 | 24.4±3.8 | 24.7±3.8 | 23.1±5.8 | 23.5±6.5 |
| LVDP(KPa) | 0.24±1.49 | 0.34±1.58 | 0.45±1.44 | 0.34±1.44 | 0.49±1.59 |
| LVEDP(KPa) | 1.23±1.70 | 1.11±1.40 | 1.21±1.31 | 1.00±1.41 | 1.06±1.66 |
| +dp/dt max(Kpa/s) | 801.1±284.0 | 836.3±185.7 | 73 1.4±172.3 | 802.0±334.0 | 847.1±266.5 |
| -dp/dt max(Kpa/s) | 815.0±105.3 | 733.1±201.3 | 746.8±124.3 | 759.4±207.7 | 786.5±180.0 |
The different Shu Ji 0.4mg/kg/h of table 19 iv to the hemodynamic effect of anesthetized dog (
N=5)
| |
0 | 10 | 30 | 60 | 120 |
| HR (inferior/minute) | 197.3±36.5 | 198.6±30.3 | 209.8±31.7 | 204.7±33.7 | 171.5±34.6 |
| BPs(KPa) | 26.8±1.2 | 25.3±1.7 | 24.8±1.3 * | 24.9±0.7 * | 25.4±1.0 |
| BPm(KPa) | 21.5±0.7 | 20.6±1.0 | 20.4±0.8 | 20.5±0.7 | 20.7±0.8 |
| BPd(KPa) | 18.9±0.6 | 18.4±0.7 | 18.1±0.7 | 18.2±0.7 | 18.4±0.8 |
| LVSP(KPa) | 24.1±0.9 | 22.9±1.3 | 23.0±0.4 | 23.0±0.8 | 22.7±0.6 |
| LVDP(KPa) | -0.29±0.42 | -0.37±0.39 | -0.17±0.34 | -0.42±0.26 | -0.47±0.21 |
| LVEDP(KPa) | 0.51±0.13 | 0.58±0.20 | 0.63±0.16 | 0.39±0.21 | 0.41±0.08 |
| +dp/dt max(Kpa/s) | 1081.0±334.0 | 1047.5±266.3 | 1123.9±225.3 | 1124.6±228.4 | 972.5±925.8 |
| -dp/dt max(Kpa/s) | 816.1±121.2 | 786.5±128.2 | 718.2±103.5 | 751.1±153.7 | 741.9±102.4 |
Table 20 TSG 2.5mg/kg iv to the hemodynamic effect of anesthetized dog (
N=5)
| |
0 | 10 | 30 | 60 | 120 |
| HR (inferior/minute) | 163.7±21.1 | 160.4±18.4 | 161.7±18.0 | 171.1±18.8 | 170.5±16.1 |
| BPs(KPa) | 25.3±3.0 | 24.5±2.0 | 24.7±1.3 | 25.5±1.6 | 23.7±3.3 |
| BPm(KPa) | 21.1±2.0 | 20.7±2.1 | 20.8±1.7 | 21.6±2.0 | 20.2±2.3 |
| BPd(KPa) | 18.5±1.7 | 18.3±2.3 | 18.5±2.2 | 19.1±2.5 | 18.1±1.8 |
| LVSP(KPa) | 24.9±4.0 | 25.2±4.2 | 25.7±3.8 | 26.5±2.5 | 26.7±2.3 |
| LVDP(KPa) | 0.39±2.20 | 0.45±2.40 | 0.28±2.40 | 0.26±2.35 | 0.50±2.06 |
| LVEDP(KPa) | 1.14±2.18 | 1.00±2.33 | 1.11±2.50 | 0.78±2.37 | 1.09±2.16 |
| +dp/dt max(Kpa/s) | 853.1±321.1 | 829.1±308.3 | 869.6±235.9 | 993.9±206.2 | 957.9±190.0 |
| -dp/dt max(Kpa/s) | 772.0±201.0 | 777.3±241.8 | 873.9±236.8 | 905.9±207.8 | 852.5±159.6 |
Table 21 TSG 5mg/kg iv to the hemodynamic effect of anesthetized dog (
N=5)
| |
0 | 15 | 30 | 60 | 120 |
| HR (inferior/minute) | 177.2±35.5 | 171.0±35.6 | 170.0±35.5 | 178.0±29.5 | 170.2±37.1 |
| BPs(KPa) | 25.4±6.4 | 25.4±5.8 | 26.1±5.3 | 26.6±4.1 | 25.0±5.0 |
| BPm(KPa) | 21.1±4.7 | 21.1±4.7 | 21.7±4.2 | 22.1±3.3 | 21.0±4.4 |
| BPd(KPa) | 18.9±4.2 | 18.7±4.4 | 19.2±4.0 | 19.8±3.3 | 18.8±4.4 |
| LVSP(KPa) | 24.1±4.4 | 24.3±4.6 | 24.6±4.6 | 25.6±3.0 | 25.1±5.2 |
| LVDP(KPa) | 0.31±1.31 | -0.09±2.03 | 0.18±1.64 | 0.09±1.29 | 0.27±1.50 |
| LVEDP(KPa) | 1.05±1.34 | 1.08±1.62 | 1.19±1.76 | 0.99±1.19 | 0.98±1.42 |
| +dp/dt max(Kpa/s) | 822.6±353.8 | 793.8±299.0 | 855.5±296.5 | 936.1±199.9 | 921.4±327.1 |
| -dp/dt max(Kpa/s) | 866.2±350.7 | 812.2±308.9 | 912.3±318.8 | 891.5±261.8 | 872.0±291.7 |
Table 22 TSG 10mg/kg iv to the hemodynamic effect of anesthetized dog (
N=5)
| |
0 | 10 | 30 | 60 | 120 |
| HR (inferior/minute) | 212.5±31.3 | 209.7±33.4 | 210.2±33.8 | 207.1±38.1 | 205.6±50.2 |
| BPs(KPa) | 28.5±7.5 | 32.4±8.2 | 33.2±8.5 | 33.6±5.5 | 29.0±4.8 |
| BPm(KPa) | 22.5±4.8 | 24.5±5.9 | 25.1±5.9 | 24.4±5.1 | 22.7±3.0 |
| BPd(KPa) | 19.6±3.7 | 21.0±5.1 | 21.4±5 5 | 20.6±4.8 | 20.2±3.0 |
| LVSP(KPa) | 30.1±5.9 | 32.4±6.3 | 32.4±6.8 | 31.7±5.5 | 29.5±2.7 |
| LVDP(KPa) | -1.18±1.71 | -1.30±2.12 | -1.25±2.47 | -1.87±2.00 | -1.04±2.11 |
| LVEDP(KPa) | 0.99±0.60 | 0.93±0.50 | 0.78±0.43 | 0.63±0.44 | 1.69±2.78 |
| +dp/dt max(Kpa/s) | 1455.5±637.7 | 1646.2±807.8 | 1623.9±729.5 | 1518.5±708.1 | 1266.6±334.8 |
| -dp/dt max(Kpa/s) | 1164.1±488.8 | 1200.6±447.6 | 1120.4±357.8 | 1189.6±461.6 | 1068.5±208.6 |
Embodiment 7 is oral 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside is to the therapeutical effect of rat chronic myocardial ischemia
The purpose of present embodiment is to observe 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside (TSG) gastric infusion is to the therapeutical effect of rat chronic myocardial ischemia.
Trial drug
3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside granule (lot number 031011), Shenzhen Haiwang Pharmaceutical Co., Ltd's preparation.Be 2 and the suspension of 4mg/ml with the 0.8%CMC compound concentration during administration.
Experimental animal
The SD rat, male, body weight 250～300 grams.No.1 Military Medical Univ. Animal Experimental Study center provides.
Experimental technique
(1) animal surgery and coronary artery ligation: 60 of male SD rats, divide two groups, 15 of sham operated rats, 45 of operation groups.Urethane (100mg/kg ip) anesthesia is faced upward the position and is fixed.Electrocardiograph (ECG-6851C, Shanghai Photoelectricity Medical electron Instrument Co., Ltd.) record II lead electrocardiogram.Tracheal intubation connects artificial respirator.Behind the skin degerming, breast left side example the 4th intercostal is opened breast, exposes heart, in ramus descendens anterior arteriae coronariae sinistrae root 3～4mm place's ligation.The electrocardiogram synchronous monitoring, with electrocardiogram S-T section obviously raise or force down, the T wave height alarms as coronary ligation success index.After the ligation, close the thoracic cavity, extract gas in the thoracic cavity out.Postoperative continues conventional the raising.Postoperative intramuscular injection penicillin prevention infection in 1 week.Sham operated rats row open chest surgery, but not ligation arteria coronaria.
(2) 5 weeks behind grouping and the art of medicating, 11 of sham operated rats surviving animals.24 of operation group surviving animals.The operation group is divided into two groups more at random, i.e. ischemic control group, 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside 20mg/kg administration group.Began in the 6th week to 6 weeks of treated animal successive administration, administration is 6 days weekly, the drug withdrawal on Sunday.The administration capacity is 5ml/kg.
(3) the 12nd week was detected behind the curative effect detection technique.Behind the last administration 30min, rat lies on the back fixing, the circulation of qi promoting cannula; Separate femoral catheter record arteriotony, cardiac catheter is driven in the wrong direction from right carotid and is inserted left ventricle.Two conduits connect pressure transducer, and pressure signal is connected to Powerlab system 8s physiograph (ML785/8S, AD Instruments, Australia) record after carrier wave amplifies.The subcutaneous insertion needle electrode of extremity monitoring standard two lead electrocardiogram.Data are monitored and stored to computer (chart4.12 software, ML785/8S, AD Instruments, Australia) in real time.Behind the operative stabilization 30min, observe heart rate (HR), mean arterial pressure (BPm), left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), the maximum rate of change of left ventricular systolic pressure (+dp/dtmax), ventricular end diastolic pressure (LVEDP), electrocardiogram.After 1 hour, put to death animal, win left ventricle, the myocardium sheet that the anxious one-tenth～5mm in a left side is thick is cleaned with normal saline, puts 37 ℃ of 0.025% chlorination nitro blue tetrazolium (Nitro-tetrazolium Blue chloride, N-BT, Switzerland Fluka chemical reagents corporation produces NBT) liquid dyeing.。Normal myocardium dyes and is skipper, and the infarct cardiac muscle then is not colored as light yellow.Under anatomical lens, separate infarct, weigh respectively, account for the percentage ratio (%) of myocardium weight as the index of weighing infarction size with infarct cardiac muscle weight.
Experimental result with
Non-paired t test method statistics is adopted in expression, and P＜0.05 o'clock thinks to have notable statistics difference.
Result of the test
Heart rate does not have significant difference between sham operated rats, ischemic control treated animal and the administration treated animal; The mean arterial pressure of ischemic control treated animal reduces sham-operation, and TSG administration treated animal blood pressure recovers the sham operated rats level.Raising or pressing at the end in various degree all appears in the ST section in the electrocardiogram of ischemia group and administration treated animal, illustrates to have myocardial ischemia.Ischemic control treated animal LVDP raises than matched group, LVESP, ± the dp/dtmax reduction; And the corresponding hemodynamic index of administration group all makes moderate progress, and the ischemic infarction tissue significantly reduces.Result of the test shows, 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside (TSG) gastric infusion has significant therapeutical effect to the rat chronic myocardial ischemia.Result of the test sees Table 23.
Table 23 TSG gastric infusion is to the therapeutical effect of rat chronic myocardial ischemia
| Sham operated rats | The ischemic control group | TSG administration group | |
| n | 11 | 12 | 12 |
| HR (inferior/min) | 364±32 | 383±52 | 354±45 Δ |
| BP(KPa) | 19.7±1.2 | 17.5±1.3 * | 19.2±1.8 Δ |
| LVSP(KPa) | 20.6±1.8 | 17.7±1.6 * | 19.8±2.1 Δ |
| LVEDP(KPa) | 0.68±0.16 | 1.09±0.25 * | 0.82±0.19 Δ |
| +dp/dt max(Kpa/s) | 1456±223 | 1106±164 * | 1389±142 Δ |
| Infarct ratio (%) | -- | 14.5±2.3 | 5.9±1.2 ΔΔ |
*P＜0.05 vs sham operated rats;
ΔP＜0.05,
The Δ ΔP＜0.01 vs ischemic control group
Embodiment 8 mouse mainlines 3,4 ', the acute toxicity test of 5-trihydroxy stilbene-3-β-D-glycoside
The purpose of present embodiment is to observe mouse mainline 3, and 4 ', the acute toxic reaction behind 5-trihydroxy stilbene-3-β-D-glycoside.
Be subjected to reagent thing 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside solution (TSG solution, lot number 03030302), 100mg/10ml; Shenzhen Haiwang Pharmaceutical Co., Ltd.During use, dilute with normal saline.
The experimental animal Kunming mouse, male and female half and half, body weight 18～22g is provided by No.1 Military Medical Univ.'s Experimental Animal Center.
Capacity such as this test of administering mode employing are isoconcentration mode intravenous administration not.Volume injected is 20ml/kg.
Test method is selected 40 of healthy kunming mices, is divided into 4 groups at random, and dosage is respectively 300mg/kg, 425mg/kg, 600mg/kg and 850mg/kg, disposable tail vein injection administration.Observed 4 hours continuously after the administration, after this every morning, afternoon, each observed once continuous 7 days.Record mice poisoning manifestations and death time, the Bliss method is calculated LD
50And 95% fiducial limit.
Can occur after the disposable tail vein injection administration of result of the test mice swaying, or reaction such as dry moving, tic appears, symptom increases the weight of with dosage.Animal dead occurred in behind the drug administration by injection after 5 minutes in 1 day.Dead animal does not recover after 2 days normally, well-grown thereafter, general activity and ingest normal.All dead animal gross anatomy main organs no abnormality seens.LD
50And 95% fiducial limit sees Table 1.
The acute toxicity testing result (n=10) of table 24 mouse mainline TSG
| Dosage (mg/kg) | Log10 dose (x) | Death toll (only) | Mortality rate (%) | LD 50And 95% fiducial limit (g/kg) |
| 360 | 2.556 | 0 | 0 | LD 50=648.94 95% crediblely be limited to 571.18～726.70 |
| 510 | 2.708 | 1 | 10 | |
| 720 | 2.857 | 7 | 70 | |
| 1020 | 3.009 | 10 | 100 |
The LD of conclusion (of pressure testing) mouse mainline TSG
50Be 648.94mg/kg, its credible 571.18mg/kg～726.70mg/kg that is limited to of 95%.
The quiet notes 3,4 ' of embodiment 9 dog single doses, the pharmacokinetics of 5-trihydroxy stilbene-3-β-D-glycoside
The purpose of present embodiment is to observe single dose 3, and 4 ', 5-trihydroxy stilbene-3-β-D-glycoside (TSG) iv is at the intravital pharmacokinetic parameter of dog.
Be subjected to the reagent product
3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside solution (lot number 03030302), 100mg/10ml; Shenzhen Haiwang Pharmaceutical Co., Ltd.During use, dilute with normal saline.
Laboratory animal
Adult, healthy Beagle dog, male and female dual-purpose, body weight 10.8～10.5Kg; Provide by the The 2nd Army Medical College Experimental Animal Center.
Experimental technique
Test is provided with 10mg/Kg, 20mg/Kg, three dosage groups of 30mg/Kg are carried out pharmacokinetic.Each dosage group is selected 5 adult, healthy Beagle dogs for use.After being tried Beagle dog overnight fasting (fasting 14 hours), in morning 8:00 intravenous administration TSG 10mg/Kg, 20mg/Kg, 30mg/Kg, administration capacity 0.5ml/Kg slowly injects into blood in Canis familiaris L. one side forelimb 5min.Can take food to being tried the Beagle dog in 3 hours after the quiet notes administration.In the test, before administration and after the administration 0,5,10,20,40,60,90,120,180,240,300,360 and 480min get blood 3ml at Beagle dog opposite side forelimb vein, put in the heparinization test tube, centrifugal, divide and to get 1.0ml blood plasma.Press Beagle dog plasma sample pretreating method operation (wherein the high concentration plasma sample needs through blank Beagle dog plasma dilution behind the quiet notes administration of the single dose TSG), measure TSG concentration in the blood plasma.
Data analysis
Adopt non-compartment model method to analyze (statistics moments method), the relevant parameters estimation equation is as follows:
AUC
0～τ＝∑(C
i+C
i-1)×(t
i-t
i-1)/2
AUC
0～∞＝∑(C
i+C
i-1)×(t
i-t
i-1)/2+C
n/λ
AUMC
0～∞＝∑(C
it
i+C
i-1t
i-1)×(t
i-t
i-1)/2+C
n(1/λ
2+t
n/λ)
MRT＝AUMC
0～∞/AUC
0～∞
Cl/F＝D/AUC
0～∞
t
1/2＝0.693/λ
V
ss＝D×AUMC
0～∞/(AUC
0～∞)
2
The terminal phase elimination rate constant of curve when λ is medicine in the formula, t
nAnd C
nBe respectively and get blood point time and plasma drug level at last.Pharmacokinetic parameter tmax, Cmax get corresponding plasma sample measured value.
Experimental result
Adopt high performance liquid chromatography measured respectively 5 grow up, TSG blood drug level in the body of different time behind the quiet notes administration of the healthy Beagle dog TSG 10mg/Kg, three dosage groups of 20mg/Kg, 30mg/Kg, wherein blood drug level-time data sees Table 25.Fig. 6, Fig. 7 and Fig. 8 represent the quiet notes administration 3,4 ' of Beagle dog respectively, the average blood drug level-time graph behind 5-trihydroxy stilbene-3-β-D-glycoside (TSG) 10mg/Kg, 20mg/Kg, the 30mg/Kg.Adopt 5 of non-compartment model method estimation to grow up, the pharmacokinetic parameter behind the quiet notes administration of the healthy Beagle dog single dose TSG 10mg/Kg, three dosage groups of 20mg/Kg, 30mg/Kg lists in table 26.
Result of the test shows, the quiet notes administration 3,4 ' of healthy Beagle dog, and behind 5-trihydroxy stilbene-3-β-D-glycoside (TSG), the physiological disposition of TSG meets two-compartment model, and the curve end is eliminated the half-life (t mutually during its pharmacokinetic parameter medicine
1/2) be respectively 167.87 ± 170.90min, 151.05 ± 57.32min, 373.09 ± 372.98min.The AUC of 10mg/Kg, 20mg/Kg, three dosage groups of 30mg/Kg
0～∽Be respectively 315.42 ± 60.82 μ gmin/ml, 745.75 ± 175.84 μ gmin/ml and 1552.71 ± 227.28 μ gmin/ml, AUC and dosage are proportionate substantially, and correlation coefficient r is 0.985.
The blood drug level of different time behind the quiet notes administration of the table 25 single dose TSG (μ g/ml,
| Dosage | Time (min) | ||||||||||||
| 0 | 5 | 10 | 20 | 40 | 60 | 90 | 120 | 180 | 240 | 300 | 360 | 480 | |
| 10 mg/Kg | 22.35 ± 4.92 | 6.84 ± 1.89 | 3.88 ± 0.66 | 2.17 ± 1.19 | 1.45 ± 0.52 | 0.93 ± 0.55 | 0.52 ± 0.20 | 0.35 ± 0.10 | 0.30 ± 0.06 | 0.24 ± 0.04 | 0.17 ± 0.06 | 0.10 ± 0.04 | 0.02 ± 0.04 |
| 20 mg/Kg | 47.68 ± 6.51 | 21.82 ± 4.59 | 13.07 ± 4.17 | 8.25 ± 4.90 | 3.48 ± 1.23 | 2.36 ± 1.12 | 0.84 ± 0.60 | 0.68 ± 0.40 | 0.46 ± 0.11 | 0.35 ± 0.13 | 0.29 ± 0.08 | 0.20 ± 0.05 | 0.07 ± 0.06 |
| 30 mg/Kg | 100.72 ± 5.85 | 49.29 ± 19.52 | 26.10 ± 11.10 | 15.21 ± 7.11 | 8.02 ± 2.95 | 5.01 ± 1.63 | 1.67 ± 0.66 | 1.08 ± 0.54 | 0.62 ± 0.30 | 0.50 ± 0.2 2 | 0.33 ± 0.05 | 0.29 ± 0.05 | 0.21 ± 0.02 |
The pharmacokinetic parameter of the quiet notes administration of table 26 Beagle dog single dose TSG
| Dosage | t 1/2 (min) | MRT (min) | CI (L/min) | AUC 0～480 (μg·min/ml) | AUC 0～∞ (μg·min/ml) | Vss (L) |
| 10 mg/Kg | 167.87 ± 170.90 | 140.06 ± 124 87 | 0.03 ± 0.01 | 283.05 ± 49.85 | 315.42 ± 60.82 | 4.21 ± 3.06 |
| 20 mg/Kg | 151.05 ± 57.32 | 78.08 ± 12.24 | 0.03 ± 0.01 | 718.32 ± 179.10 | 745.75 ± 175.84 | 2.24 ± 0.78 |
| 30 mg/Kg | 373.09 ± 372.98 | 184.08 ± 240.08 | 0.02 ± 0.00 | 1432.17 ± 349.97 | 1552.71 ± 227.28 | 4.25 ± 6.35 |
3,4 ' of embodiment 10 embodiment 1～8,5-trihydroxy stilbene-3-β-D-glycoside (TSG) test specimen preparation
Among the present invention 3,4 ', it is that method in 200310112538.3 the Chinese patent application " new preparation process of polygonin and resveratrol " prepares gained that 5-trihydroxy stilbene-3-β-D-glycoside (TSG) adopts application number.
(1) 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside granule (embodiment 1,4,7 specimen in use) preparation:
Prescription:
| 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside | 20g |
| Starch | 40g |
| Microcrystalline Cellulose (PH301) | 40g |
| Granule weight | 100g |
Preparation: 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside mixes with lactose, microcrystalline Cellulose (PH301) until the mixture that forms homogeneous.Add adequate amount of ethanol-water and powder is granulated, after the drying, promptly.
(2) 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside solution ( embodiment 2,3,5,6,8,9 specimen in use) preparation:
Prescription:
| 3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside | 100g |
| Dehydrated alcohol | 8L |
| The NaOH aqueous solution of pH9 adds to | 10L |
| Be distributed into | 1000 |
Preparation: with 40g3,4 ', 5-trihydroxy stilbene-3-β-D-glycoside heating for dissolving is in the 8L dehydrated alcohol, and NaOH aqueous solution to the cumulative volume that adds pH8.5 is 10L, behind the φ 0.2 μ m filtering with microporous membrane, divides to install in 1000 ampoule bottles or the cillin bottle.
Claims (7)
1,3,4 ', the purposes of 5-trihydroxy stilbene-3-β-D-glycoside in the ischemic heart medicine due to preparation treatment or the prevention coronary stricture.
2, purposes according to claim 1 is characterized in that the ischemic heart desease due to the described coronary stricture is silent myocardial ischemia, angina pectoris, myocardial infarction, ischemic cardiomyopathy, heart failure and overworked dead.
3, purposes according to claim 1 is characterized in that describedly 3,4 ', and 5-trihydroxy stilbene-3-β-D-glycoside uses with the form of oral formulations or intravenous administration preparation.
4, contain 3,4 ', the purposes of the pharmaceutical composition of 5-trihydroxy stilbene-3-β-D-glycoside in the ischemic heart medicine due to preparation treatment or the prevention coronary stricture.
5, purposes according to claim 4 is characterized in that described pharmaceutical composition contains 3,4 ' of 20～300mg, 5-trihydroxy stilbene-3-β-D-glycoside and pharmaceutically acceptable pharmaceutic adjuvant.
6, purposes according to claim 5 is characterized in that described pharmaceutical composition contains 3,4 ' of 50～200mg, 5-trihydroxy stilbene-3-β-D-glycoside and pharmaceutically acceptable pharmaceutic adjuvant.
7, purposes according to claim 4, the dosage form that it is characterized in that described pharmaceutical composition are oral formulations or intravenous administration preparation.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100524709A CN1330311C (en) | 2004-12-01 | 2004-12-01 | Use of 3,4,5-trihydroxy stilbene-3-beta-D-gluooside in preparation of antimyocardial ischemia medicine |
| PCT/CN2005/001912 WO2006058483A1 (en) | 2004-12-01 | 2005-11-14 | USE OF 3, 4’,5-TRIHYDROXY-STILBENE-3- β-D-GLUCOSIDE IN PREPARATION OF MEDICINES FOR TREATING AND/OR PREVENTING ISCHEMIC HEART DISEASE |
| KR1020077015044A KR20070098838A (en) | 2004-12-01 | 2005-11-14 | USE OF 3,4',5-TRIHYDROXY-STILBENE-3-beta;-D-GLUCOSIDE IN PREPARATION OF MEDICINES FOR TREATING AND/OR PREVENTING ISCHEMIC HEART DISEASE |
| US11/720,451 US20080176810A1 (en) | 2004-12-01 | 2005-11-14 | Use of 3, 4', 5-Trihydroxy-Stilbene-3-Beta-D-glucoside in Prepartion of Medicines For Treating and/or Preventing Ischemic Heart Disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100524709A CN1330311C (en) | 2004-12-01 | 2004-12-01 | Use of 3,4,5-trihydroxy stilbene-3-beta-D-gluooside in preparation of antimyocardial ischemia medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1650875A CN1650875A (en) | 2005-08-10 |
| CN1330311C true CN1330311C (en) | 2007-08-08 |
Family
ID=34868734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100524709A Active CN1330311C (en) | 2004-12-01 | 2004-12-01 | Use of 3,4,5-trihydroxy stilbene-3-beta-D-gluooside in preparation of antimyocardial ischemia medicine |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20080176810A1 (en) |
| KR (1) | KR20070098838A (en) |
| CN (1) | CN1330311C (en) |
| WO (1) | WO2006058483A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1403088A (en) * | 2002-10-08 | 2003-03-19 | 深圳海王药业有限公司 | Medicine composition containing polydatin or its salt and its use in preparing medicine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6022901A (en) * | 1998-05-13 | 2000-02-08 | Pharmascience Inc. | Administration of resveratrol to prevent or treat restenosis following coronary intervention |
| US20030026855A1 (en) * | 1998-09-09 | 2003-02-06 | Kameneva Marina V. | Artificial blood fluids and microflow drag reducing factors for enhanced blood circulation |
| CN1401654A (en) * | 2002-08-07 | 2003-03-12 | 陕西赛德高科生物股份有限公司 | 3,4'-5-trihydroxystlbenes compounds with functions of reducing pulmonary artery high pressure and improving respiration function |
-
2004
- 2004-12-01 CN CNB2004100524709A patent/CN1330311C/en active Active
-
2005
- 2005-11-14 KR KR1020077015044A patent/KR20070098838A/en not_active Application Discontinuation
- 2005-11-14 WO PCT/CN2005/001912 patent/WO2006058483A1/en not_active Application Discontinuation
- 2005-11-14 US US11/720,451 patent/US20080176810A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1403088A (en) * | 2002-10-08 | 2003-03-19 | 深圳海王药业有限公司 | Medicine composition containing polydatin or its salt and its use in preparing medicine |
Non-Patent Citations (3)
| Title |
|---|
| 白藜芦醇心血管保护作用研究进展 陈莉娜等，生理科学进展，第34卷第3期 2003 * |
| 白藜芦醇心血管保护作用研究进展 陈莉娜等，生理科学进展，第34卷第3期 2003;葡萄中的功效成份-白藜芦醇，白藜芦醇苷和原花青素 夏开元等，食品科学，第23卷第8期 2002 * |
| 葡萄中的功效成份-白藜芦醇，白藜芦醇苷和原花青素 夏开元等，食品科学，第23卷第8期 2002 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1650875A (en) | 2005-08-10 |
| WO2006058483A1 (en) | 2006-06-08 |
| KR20070098838A (en) | 2007-10-05 |
| US20080176810A1 (en) | 2008-07-24 |
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